USF Health preclinical study suggests boosting cardiac SIRT1/SIRT3 levels in older heart attack patients may help protect against ischemia-reperfusion injury

Tampa, FL (Aug. 20, 2021) — Sirtuins are a family of anti-aging proteins that help regulate cellular lifespan, metabolism, and resistance to stress. The potential protective effect of these sirtuin enzymes in age-related diseases, including cardiovascular diseases, remains an area of intense investigation.

Principal investigator Ji Li, PhD, is a professor of surgery and member of the USF Health Heart Institute at the USF Health Morsani College of Medicine. | Photo by Allison Long, USF Health Communications

Now, a new preclinical study led by University of South Florida Health (USF Health) researchers has determined that sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3) levels decline in aging hearts, disrupting the ability of cardiac muscle cells (cardiomyocytes) to contract in response to ischemia-reperfusion injury (also known as reperfusion injury). Furthermore, age-related SIRT1 and SIRT3 deficiency can impair cardiac function by altering mitochondrial dynamics, which play an important role in metabolic health and inflammatory response, the researchers report.

The findings were published online July 3 in Aging Cell.

“We discovered that age-related changes in mitochondrial dynamics are caused by SIRT1/SIRT3 deficiency, specifically in the cardiomyocytes,” said principal investigator Ji Li, PhD, professor of surgery in the USF Health Morsani College of Medicine. “You need a strong presence of SIRT1 and SIRT3 to keep mitochondrial dynamics healthy in the heart. Otherwise, the heart’s pumping function becomes weak.”

Diastolic functions assessment of a mouse heart imaged with ultrasound echocardiography | Photo by Allison Long, USF Health Communications

Mitochondria produce the energy needed to drive nearly all processes in living cells. Cardiac muscle cells contain more mitochondria than any other cells, because the heart needs large amounts of energy to constantly pump blood throughout the body. Stabile mitochondrial dynamics maintain a healthy balance between the constant division (fission) and merging (fusion) of mitochondria and help ensure the quality of these specialized structures known as the “powerhouse” of the cell.

Reperfusion, a common treatment following acute heart attack, restores blood flow (and thus oxygen) to a region of the heart damaged by a blood clot blocking the coronary artery. Paradoxically, in some patients this necessary revascularization procedure triggers further injury to heart muscle tissue surrounding the initial heart attack site. No effective therapies currently exist to prevent reperfusion injury.

Research associate Di Ren, PhD (left) works with the heart perfusing system in the Department of Surgery physiology laboratory as USF undergraduate student Julia Fedorova watches. | Photo by Allison Long, USF Health Communications

To help analyze the response of cardiac mitochondria to ischemia-reperfusion stress, the USF Health researchers deleted SIRT1 or SIRT3 in cardiac muscle cells of mouse hearts, and examined the mitochondrial response to ischemic stress by restricted blood flow. They found that the mitochondria in mouse hearts lacking cardiomyocyte SIRT3 were more vulnerable to reperfusion stress than the mouse hearts with SIRT3 intact. The cardiac mitochondrial dynamics (including shape, size, and structure of mitochondria) in these knockout mice physiologically resembled that of aged wildtype (normal) mice retaining cardiac SIRT3.

Furthermore, the young mice with SIRT1 or SIRT3 removed had measurably weaker cardiomyocyte contractions and exhibited aging-like heart dysfunction when ischemia-reperfusion stress was introduced. In essence, without SIRT1/SIRT3 the hearts of these otherwise healthy young mice looked and behaved like old hearts.

“We started this study trying to understand why older people have higher incidences of heart attacks than younger people, and why they die more often even if they receive maximum treatment. Younger people are much more likely to recover from heart attacks and less likely to suffer from ischemia-reperfusion injury,” said Dr. Li, a member of the USF Health Heart Institute. “Our research suggests that one reason could be that both SIRT1 and SIRT3 are downregulated with aging. Younger people have higher levels of these proteins needed to make mitochondrial dynamics healthier.”

Dr. Li’s research team (pictured here) focuses on understanding the molecular mechanisms of coronary artery disease, the most common cause of age-related heart disease. | Photo by Allison Long, USF Health Communications

The study also suggests that, before surgically opening blocked coronary arteries to restore blood flow in older patients, administering a treatment to “rescue” (improve) their diminished SIRT1/ SIRT3 levels may increase tolerance to cardiac muscle reperfusion stress, thereby reducing heart attack complications and deaths, Dr. Li said. Such a cardioprotective treatment might apply a genetic approach to increase SIRT1/SIRT3 production, or an agonist (drug) to activate SIRT1/ SIRT3, he added.

If their mouse model findings translate to human hearts, Dr. Li’s group wants to work with companies interested in developing and testing SIRT1/SIRT3 activators to mitigate heart attack-related reperfusion injury.

“Our ultimate goal is to identify ideal targets for the treatment of heart attack, especially in older patients,” said Dr. Li, whose research is supported by grants from the National Heart, Lung, and Blood Institute, the National Institute on Aging, and the National Institute of General Medical Sciences.

A USF Health preclinical study indicates nanoparticles containing a micro-RNA switch offers promising biotechnology to advance the fight against atherosclerotic cardiovascular disease

Illustration of angioplasty with a stent

Tampa, FL (Feb. 9, 2021) – Percutaneous coronary intervention (PCI), commonly known as angioplasty with a stent, opens clogged arteries and saves lives. Despite its benefit in treating atherosclerosis that causes coronary artery disease, this common minimally invasive procedure still poses severe complications for some patients.

Angioplasty involves inflating a balloon at the tip of a catheter to compress fatty deposits (plaques) against the artery wall, thereby restoring blood flow to the narrowed or blocked vessels. The image-guided procedure is often combined with the placement of either uncoated stents — tiny expandable mesh devices– or stents coated with slowly-released antiproliferative drugs. The drug-eluting stents help avert the growth of scar tissue (smooth muscle cell proliferation) in the artery so that the vessel does not eventually close again, known as restenosis.

However, current antiproliferative drugs indiscriminately inhibit the growth of all nearby cells, including the layer of endothelial cells lining the blood vessels. These endothelial cells prevent blood clots (thrombosis) within the stent and the formation of more plaques (neoatherosclerosis), which can trigger a heart attack or sudden cardiac death.

Focused on tackling this treatment complication, University of South Florida Health (USF Health) Morsani College of Medicine researchers recently developed a next-generation nanotherapy. Their preclinical findings are detailed in a study published Feb. 2 in Molecular Therapy.

Hana Totary-Jain, PhD, USF Health associate professor of molecular pharmacology and physiology, was principal investigator for the nanotherapy study.

The nanotherapy comprised of a nontoxic peptide known as p5RHH and a synthetic messenger RNA (mRNA) that carries the genetic instructions, or code, needed by cells to make proteins. By simply mixing up the p5RHH with the mRNA, they spontaneously self assemble into compacted nanoparticles that specifically target the injured regions of the arteries in mouse models mimicking angioplasty. The nanoparticles contain an microRNA switch added to the mRNA.

“One of the main challenges of cardiovascular disease remains the delivery of targeted therapies specifically to the plaque regions and the cells that form plaques, including the smooth muscle cells and inflammatory cells — without affecting the endothelial cells or the healthy regions,” said the study’s principal investigator Hana Totary-Jain, PhD, an associate professor of molecular pharmacology physiology at USF Health Morsani College of Medicine.

To do this, the researchers used mRNA that encodes for p27 protein, which blocks cell growth, and added to the mRNA an endothelial cell-specific microRNA to generate a microRNA switch. The design of this microRNA switch allowed the researchers to turn on the mRNA in smooth muscle cells to inhibit their growth and the formation of restenosis. It also enabled them to turn off the mRNA in endothelial cells so these cells could grow uninhibited and quickly heal the damaged blood vessel.

John Lockhart, PhD, was the paper’s lead author.

“If we can come up with an antiproliferative therapy that specifically targets the cardiovascular smooth muscles cells and the infiltrating inflammatory cells but spares the endothelial cells – which we’ve done with the design of our microRNA switches – then we should be able to achieve the therapeutic effects of drug-eluting stents without the downside of thrombosis and neoatherosclerosis,” said the paper’s lead author John Lockhart, PhD, who worked on the study as a doctoral student at USF Health Molecular Pharmacology and Physiology. Dr. Lockhart is continuing his postdoctoral training at Moffitt Cancer Center.

The latest study builds upon previous research by Dr. Totary-Jain, indicating that a microRNA-based therapy worked better than drug-eluting stents in a rat model of angioplasty. That work used an adenovirus vector to carry the cell-selective therapy to injured arteries. In this study the viral vector was replaced with a nanoparticle alternative – a change needed to avoid safety concerns and advance the therapy toward use in patients.

The investigational nanoparticles were injected into mice with arteries mimicking post-angioplasty vessel injury every three days for two weeks (5 doses total). Mice treated with the nanoparticles containing the miRNA switch had significantly reduced restenosis and completely restored endothelial cell growth in the injured artery, compared to animals treated with nanoparticles containing mRNA without the miRNA switch, the researchers report.

Above: Injured control artery treated with near infrared florescent protein, depicts restenosis in center. Below: Injured artery treated with the microRNA switch nanotherapy shows open artery (no restenosis) and clear endothelial cell layer marked in green. | Images courtesy of Hana Totary-Jain, USF Health

In addition, the nanoparticles efficiently delivered its mRNA cargo, without degradation, solely to regions of the artery where endothelial cells were damaged. The particles did not toxically accumulate either in the cells of healthy organs (the liver, spleen. lungs or kidneys), or in uninjured arteries adjacent to those requiring treatment. The researchers observed no adverse reactions or outcomes in mice treated with the nanoparticles.

Overall, the findings suggest that the miRNA-switch nanoparticles could be applied clinically to selectively prevent restenosis after PCI by specifically targeting areas of endothelial cell damage to allow quicker cell regrowth and repair of injured arteries.

The USF Health researchers next plan to investigate the potential of the microRNA-switch nanoparticles to directly treat atherosclerotic plaques, thereby eliminating the need for PCI.

“Cardiovascular disease is still the number one cause of death,” said Dr. Totary-Jain, a member of the USF Health Heart Institute. “This research offers promise for the development of novel biomolecular therapies to advance the fight against coronary artery disease and peripheral artery disease,”

One person dies of cardiovascular disease every 36 seconds in the U.S., according to the Centers for Disease Control and Prevention.

The USF Health research was supported by grants from the National Institutes of Health. Samuel Wickline, MD, director of the USF Health Heart Institute, and Hua Pan, PhD, assistant professor at the Heart Institute, collaborated on the study.

In search of individualized heart failure therapies, Ganesh Halade leads a USF Health Heart Institute team studying unresolved inflammation after heart attack

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Short-term inflammation is one of the body’s key defense mechanisms to help repair injury and fight infection. But low-level inflammation that does not subside has been linked to many common chronic conditions, including cardiovascular diseases such as atherosclerosis, atrial fibrillation and heart failure.

Ganesh Halade, PhD, an associate professor of cardiovascular sciences at the USF Health Morsani College of Medicine, investigates the safe clearance of acute inflammation – and what happens at the molecular and cellular levels when initially beneficial inflammation becomes harmful to the heart.  His team at the USF Health Heart Institute works on bridging the gap between the immune-responsive metabolism of fat and cardiac health by more clearly defining two distinct but simultaneous processes: the inflammatory response and how inflammation is safely cleared, or resolved.

In particular, Dr. Halade’s laboratory focuses on discovering ways to prevent, delay or treat the unresolved inflammation after a heart attack, which plays a key role in the pathology leading to heart failure. Their goal is to contribute to individualized therapies that may account for possible sex, racial/ethnic or age-related physiological differences in heart failure, a leading cause of hospitalizations and deaths worldwide.

Ganesh Halade, PhD, associate professor of cardiovascular sciences, joined the USF Health Heart Institute in February 2020. [Photo by Allison Long, USF Health Communications]

“Although several treatments and devices exist to help manage heart failure, the challenge remains the growth of metabolic risk factors like obesity, diabetes, hypertension and aging that amplify heart failure – and inflammation underlies all these conditions,” Dr. Halade said. “We’re in the early stages of understanding how the inflammatory response becomes chronic, or unresolved” after heart attack-induced injury.

Honing in on “the roots”

Dr. Halade’s late father, a farmer in Nashik close to Mumbai, India, emphasized to his young son that if he wanted to make a difference in life to “look to the roots, rather than the fruits.”

That philosophy drives Dr. Halade’s research endeavors. “We focus on the root causes of inflammation so that we can successfully treat the chronic inflammation that leads to heart failure,” he said.

Dr. Halade (center) with his research team, postdoctoral fellow Bochra Tourki, PhD, (left) and research associate Vasundhara Kain, PhD, (right). [Allison Long, USF Health Communications]

Clinical trials of several anti-inflammatory therapies so far have failed to show benefit in heart failure patients. Dr. Halade suggests that the investigational compounds intended to suppress inflammation very early in the cardiovascular disease process likely disrupt the tight control of immune-responsive signaling needed for timely resolution of inflammation.

“The inflammatory response and its resolution are two sides of the same coin – and they roll together. Blocking one side will affect the other,” he explained. “So, we don’t want to block the ‘get in signal’ needed to promote the early, ‘good’ inflammation. We want to accelerate the ‘get out’ signal to immune cells, so that as soon as repair of cardiac injury is done the acute inflammation leaves without becoming chronic.”

Dr. Halade views a high-resolution image (below) of a normally beating heart. [Photos by Anne DeLotto Baier, USFH Research Communications]

Connecting dysfunctional inflammation control and heart failure

A class of immune-system molecules orchestrates the resolution of tissue inflammation, an active process essential for advancing cardiac healing after a heart attack. These specialized proresolving mediators, or SPMs, are signaling molecules that form when fatty acids metabolize in response to immune activation of leukocytes.

Dr. Halade’s work is helping uncover new details on how heart failure-inducing inflammation may be limited (without promoting immunosuppression) – either by administering pharmacological SPMs, or activating enzymes that help stimulate the body’s own SPMs.

Over the last two years, he has published significant findings in several leading journals (papers summarized below) making the connections between fatty acids, inflammation control, and heart failure. Among Dr. Halade’s study collaborators is Charles Serhan, PhD, of Harvard Medical School, a pioneer in the emerging field of inflammation resolution.

• Science Signaling: This study followed the time course of inflammation and its resolution in a mouse heart attack model. The research showed for the first time that the active inflammation-resolving phase coincided with the acute inflammatory response facilitating cardiac repair after a heart attack. Among other factors, the researchers looked at types and amounts of SPMs, and the expression of enzymes that synthesize SPMs, both in the spleen and at the injured site of the heart. Macrophages, a type of white blood cell, are needed to generate SPMs as opposed to other immune cells, they reported.

Dr. Halade’s laboratory focuses on discovering ways to prevent, delay or treat the unresolved inflammation after a heart attack, which plays a key role in the pathology leading to heart failure. [Anne DeLotto Baier]

• Journal of the American Heart Association: The preclinical study discovered male-female cardiac repair differences in heart failure survival after heart attack, including improved recovery of cardiac function and greater survival of acute and chronic heart failure in female mice. Females generated higher levels of a particular fatty acid-derived signaling molecule (EET; epoxyeicosatrienoic acids) known to facilitate healing after a heart attack.

• ESC Heart Failure: The researchers profiled bioactive lipids (inflammatory biomarkers) in blood samples from hospitalized Black and White patients soon after a severe heart attack. They found a potent SPM signature (resolvin E1) was significantly lower in Black men and women than in Whites. The study concluded bioactive lipids are key for the diagnosis and treatment of cardiac repair after heart attack to delay heart failure.

• The FASEB Journal: Halade and colleagues identified a mouse model to study heart failure with preserved ejection fraction (HFpeF), a common form of heart failure linked to age-related obesity. Using this unique model of obese aging, they defined how the deficiency of a single resolution receptor triggers obesity in mice at an early age, which can give rise to many of the molecular and cellular processes ultimately leading to HFpEF.

Vasundhara Kain (seated) and Bochra Tourki, look at slides for a paper on age-related obesity and heart failure. [Allison Long, USF Health Communications]

Insight into potential inflammation-resolving therapies

As they learn more about the metabolic and immune-responsive signals that control acute cardiac inflammation, researchers hope to harness the capacity of fatty acid-derived bioactive molecules to prevent, diagnose and treat heart failure, Dr. Halade said. SPMs are derived primarily from omega-3 fats in our diet – the polyunsaturated “good” fats in foods like salmon, avocados, almonds, and walnuts.

Some evidence indicates that omega 3-rich diets and/or SPM supplements, as well as getting enough exercise and quality sleep may help prevent the unresolved inflammation leading to heart failure, Dr. Halade said. If SPMs are not produced due to risk factors like obesity or aging, or because enzymes required to metabolize fatty acids are deficient, then drugs specifically designed to facilitate cardiac repair and calm inflammation might delay or treat heart failure, he added. Distinctive biochemical signatures acquired by analyzing SPMs or other metabolites might even be used to help diagnose heart failure or predict which treatments will work best for certain patients.

Dr. Halade joined USF Health this February from the University of Alabama at Birmingham, where he was a faculty member since 2013. He received his PhD in pharmacology from the University of Mumbai Institute of Chemical Technology in 2007. He completed two postdoctoral fellowships at the University of Texas Health Science Center in San Antonio. The first fellowship focused on nutritional immunology. The second was conducted with mentor Merry Lindsey, PhD, to examine the effects of obesity on post-heart attack cardiac structure and function.

Foods rich in omega-3 fatty acids (including salmon, walnuts and avocados), as well as enough exercise and quality sleep, may help prevent unresolved inflammation contributing to cardiovascular disease.

Dr. Halade’s research is supported by funding from the NIH’s National Heart, Lung and Blood Institute. In 2018, he received American Physiological Society Research Career Enhancement Award to train in lipidomics at the RIKEN Center for Integrative Medical Sciences in Japan.

His inflammation resolution research has been recognized with two awards for studies published in the American Journal of Physiology-Heart and Circulatory. An Article Impact Award 2020 was conferred this March by the American Physiological Society for Dr. Halade’s work defining the impact of the cancer drug doxorubicin on the heart and spleen. He also received a 2017 Best Paper Award from the Unbound Science Foundation. Dr. Halade is associate editor for the American Journal of Physiology-Heart and Circulatory and for Scientific Reports, and serves on the editorial boards of several other high-impact journals in cardiovascular sciences.

At left: Beneficial resolution of inflammation following cardiac repair. At right: Risk factors like aging, obesity and some medications can contribute to unresolved (chronic) inflammation, which impairs cardiac repair and can lead to heart failure. [Graphic courtesy of Ganesh Halade]

Some things you may not know about Dr. Halade

• As an undergraduate student in India, Dr. Halade won the gold medal in fencing at a statewide collegiate competition.
• To help promote a heart healthy lifestyle, he enjoys recreational bicycling and gardening in his backyard, where he grows vegetables and chiles.
• Halade lives in Tampa with his wife Dipti, an information technology engineer, and their son Arav, 13.

Top:  Sources of inflammation include injury (like damage from a heart attack), infection (viruses, bacteria or other pathogens), and factors associated with lifestyle (such as poor diet and lack of exercise). Below: Ways to help prevent unresolved cardiac inflammation associated with lifestyle. [Graphics courtesy of Ganesh Halade]

-Video by Allison Long, USF Health Communications and Marketing

The USF Health study, using a rat model for high blood pressure, helps explain the different nerve-induced physiological response to air pollution in patients with preexisting cardiovascular disease

Numerous studies have linked air pollution with cardiovascular disease, including evidence suggesting that chronic exposure accelerates the process of atherosclerosis.

TAMPA, Fla. (June 18, 2019) — Air pollution significantly increases the risk for premature deaths, particularly in people with underlying cardiovascular disease, clinical and epidemiological studies have determined

In healthy people, inhaling ozone or particle pollution triggers a defensive lung-heart reflex (pulmonary-cardiac reflex) that automatically slows heart rate to accommodate oxygen deficiency and help slow distribution of pollutants throughout the body. Yet, when patients with cardiovascular diseases breathe pollutants that same protective mechanism does not kick in.  Instead, their heart rates intermittently speed up, known as tachycardia, and can evoke a potentially deadly irregular heart rhythm, known as premature ventricular contractions.

What accounts for the difference?  University of South Florida Health (USF Health) researchers who study the role of sensory airway nerves in protective behaviors wanted to know.

Their preclinical findings, reported May 11 in The Journal of Physiology, help explain the altered physiological response to air pollution in patients with preexisting cardiovascular disease.

Thomas Taylor-Clark, PhD, of the USF Health Department of Molecular Pharmacology and Physiology, was senior author for the study.| Photo by Eric Younghans

Using a rat model for high blood pressure (hypertension), a common chronic cardiovascular condition, the USF Health team found that preexisting hypertension altered normal reflexes in the lungs to affect autonomic regulation of the heart when an irritant mimicking air pollution was inhaled. In particular, hypertension appeared to shift the reflex response from the parasympathetic nervous system to the sympathetic nervous system.  The sympathetic nervous system mobilizes the body’s defensive “fight-or-flight” response to a threat, including releasing adrenaline that increases heart rate. In contrast, the parasympathetic nervous system controls involuntary responses, including breathing and heart rate, while the body is at rest and maintains a state of calm.

“The speeding up of heart rate and abnormal heart beats (in the hypertensive rats) were due to the switching on of this ‘flight-or-fight’ nervous system not seen in the healthy animals exposed to noxious agents,” said senior author Thomas Taylor-Clark, PhD, associate professor of molecular pharmacology and physiology in the USF Health Morsani College of Medicine. “The heart was responding to an aberrant nerve-generated reflex that may worsen preexisting cardiovascular disease.”

To simulate effects of air pollution inhaled into the lungs — difficult to recreate in a laboratory setting — the USF researchers used allyl isothiocyanate, the pungent ingredient in wasabi and horseradish.  When healthy rats with normal blood pressure inhaled this irritant, their heart rates slowed as expected.  But, in the rats with chronic hypertension, inhaling the same irritant stimulated an increased heart rate accompanied by premature ventricular contractions.

Surprisingly, a rapid heart rate and abnormal heart rhythm did not occur when allyl isothiocyanate was intravenously injected into the hypertensive rats.

USF Health postdoctoral scholar J. Shane Hooper, PhD, was the study lead author.

“It did not evoke the peculiar reflex; instead, we observed a slowing of the heart rate like that seen in the rats with normal blood pressure,” Dr. Taylor-Clark said. “This suggests that the sensory airway nerves accessible by IV are different than those accessible by inhalation… so perhaps the pathways of airway sensory nerves (connecting organs like the heart and lungs with the brainstem,) are more complex than previously understood.”

Chronic hypertension may remodel airway sensory nerves controlling the pulmonary-cardiac reflex that helps defend the body against physical damage from air pollution, the USF study suggests. This remodeling, which may happen in the developmental stages of hypertension, could turn on inappropriate sympathetic nervous system excitation of the heart, Dr. Thomas-Taylor said.

By better understanding how cardiovascular disease changes neuronal interactions between the heart and lungs, the researchers hope to help doctors with treatment choices – and eventually discover new treatments.

“Our goal is to add another piece of information that clinicians could consider when selecting a best treatment for hypertension. In addition to the patient’s age, ethnicity and race, that might include whether the person lives in an area with high pollution levels,” he said. “In the long-term, if we can identify the nervous system mechanisms involved in remodeling the pulmonary-cardiac reflex, we can target those to develop new blood pressure drugs.”

The USF Health study was supported by grants from the American Heart Association, the National Institutes of Health’s National Heart, Lung and Blood Institute, and the NIH Commonfund.

A slice of the brainstem showing central projections of defensive nerves (red) into the medulla, where the nerves transmit signals to brainstem networks to control various involuntary functions like breathing, cough, swallowing, heart rate and blood pressure.

More than four in 10 Americans are at risk of disease and premature death due to air pollution, the American Lung Association reports. And, more than one-third of the deaths from lung cancer, heart disease and stroke are associated with air pollution, according to the World Health Organization.

Preclinical cancer study has implications for inhibiting atherosclerotic plaque growth

Uncontrolled angiogenesis (new blood vessel growth) plays a critical role in the growth and spread of cancer. | Image courtesy of The Angiogenesis Foundation

The formation of new blood vessels, known as angiogenesis, is essential for embryonic tissue development, wound healing and regenerative functions.  But when this normal process goes awry, the oxygen and nutrients carried though blood vessels can spur tumor cells to multiply uncontrollably and lead to cancer in distant tissues.

Cancer medications inhibiting excessive growth of new blood vessels frequently target vascular endothelial growth factor (VEGF), the main driver of blood vessel formation in tumors.  While VEGF inhibitors have been a breakthrough in treating many cancers, the medications also cause cardiotoxic side effects, such as hypertension and blood clots, in some patients.

Seeking to improve selective targeting of tumor-associated vessels and the safety profile of anti-angiogenesis therapy, a team of scientists, including USF Health Heart Institute Director Samuel Wickline, MD, investigated the role of the developmentally critical transcription factor Etv2 in tumor angiogenesis. VEGF signaling helps blood vessels survive and maintain stability when disease is not present in addition to regulating tumor angiogenesis. But, Etv2 appears to be expressed only in cancer tissue in adults, making the molecular control mechanism an attractive target, said Dr. Wickline, a professor of cardiovascular sciences and medical engineering at USF Health Morsani College of Medicine.

Findings of the preclinical study, led by Washington University School of Medicine in St. Louis, were reported last year in JCI Insight.

Testing a new target

The researchers found that optimal tumor growth requires reactivation of dormant Etv2, and Etv2-deficient tumor blood vessels resembled normal, stable vessels when mice without tumors were compared to those in which the Etv2 gene was knocked out (disabled). They then injected into tumor-bearing mice nanoparticles carrying small interfering RNA (siRNA) specifically designed to hit and silence Etv2, with the intent of switching off the signaling needed to feed the tumor’s blood supply and fuel VEGF-induced tumor growth.

The treatment worked to block tumor angiogenesis without creating cardiovascular side effects associated with VEGF inhibitors.  More research is needed, but the study authors concluded that combining Etv2 inhibition with chemotherapy or immunotherapy may improve future cancer treatments.

Samuel Wickline, MD, director of the USF Health Heart Institute, and USF Health biomedical engineer Hua Pan, PhD, design nanoparticles to precisely deliver therapeutic molecules to specific cell types associated with inflammatory diseases.

A balance of signals circulating in the microenvironment around each cell tightly regulates angiogenesis.  When no longer needed to establish the cardiovascular system and drive blood supply to the embryo’s developing organs, angiogenesis switches off. In adults, angiogenesis primarily switches on for a limited time to restore blood flow to tissues or organs after injury.  A hallmark of cancer, however, is an angiogenesis switch that never turns off.

“While a tumor (early cancer) is still growing slowly we want to turn off angiogenesis to prevent new blood vessel growth and metastasis,” Dr. Wickline explained. “The idea behind this particular nanotechnology targeting Etv2 is that the treatment selectively inhibits the angiogenesis associated with cancer progression, and not other physiological angiogenesis processes that are needed for repair of tissues anywhere else in the body.”

Potential applications for atherosclerosis

Dr. Wickline’s laboratory built the nanoparticle peptide-siRNA structure capable of precisely delivering a message to silence Etv2 in tumors.  That same nontoxic delivery system can carry other therapeutic molecules to various specific cell types in the body associated with inflammatory diseases, including cardiovascular disorders.

The researchers plan to test whether Etv2 may also be a good nanotherapy target for blocking angiogenesis in atherosclerosis, which leads to fatty plaques building up in the arteries. That’s because abnormal blood vessel growth also provides nutrients to the inflammatory cells inside atherosclerotic plaques and plays a crucial role in plaque rupture that can cause heart attacks and stroke.

“Just like inhibiting angiogenesis starves a tumor of its blood supply,” Dr. Wickline said, “we also want to find ways to starve plaques of the blood supply to keep them from getting bigger and more dangerous.”

Dr. Christian Bréchot will help elevate biomedical and health-related areas of research excellence to the international level

The former head of the world-renowned Pasteur Institute in Paris has joined USF Health to help university leaders strengthen biomedical and health-related areas of research excellence – and to elevate interdisciplinary signature programs to the international level.

Christian Bréchot, MD, PhD

Preeminent virologist Christian Bréchot, MD, PhD, joined the USF Health Morsani College of Medicine part time in October as senior associate dean for research in global affairs, associate vice president for international partnerships and innovation, and a professor in the Division of Infectious Disease, Department of Internal Medicine.  Dr. Bréchot is also executive director of the Tampa-based Romark Laboratories Institute for Medical Research. Since 2017, he has served as president of the Global Virus Network, a coalition of the world’s foremost medical virologists.

“Dr. Bréchot has been at the forefront of catalyzing teams of top scientists to work together effectively on global solutions for emerging pathogens, malaria and microbial infections,” said Charles Lockwood, MD, senior vice president for USF Health and dean of the Morsani College of Medicine. “He is the ideal person to work with leadership across USF Health and USF in strategically identifying opportunities to take our infectious diseases, cardiovascular, neuroscience, and maternal-child health translational research to the next level, and to build upon the international networks he helped create at the Pasteur Institute and elsewhere to make that happen.”

Before serving as president of the Pasteur Institute from 2013 to 2017, Dr. Bréchot was vice president of medical and scientific affairs at Institut-Merieux, a company that develops new approaches to fight infectious diseases and cancers.  He also served as the general director of Inserm, the French national agency for biomedical research (analogous to the National Institutes of Health in the U.S.) from 2002 to 2007. As professor of hepatology and cell biology at Necker School of Medicine, Paris Descartes University, he headed the clinical department of liver diseases at Necker-Enfants Maldes Hospital from 1997 to 2001.

Dr. Bréchot has authored more than 400 articles in medical and scientific journals, and in 2005 was ranked by the Institute for Scientific Information as the 4^th most cited author on the topic hepatitis C. He has been recognized as an inventor on 18 patents, and helped to create three biotechnology companies.

With a prestigious career bridging basic science and medicine, Dr. Bréchot has combined research, clinical service and teaching with top administrative posts to enhance scientific understanding and better public health. His scholarly endeavors have included cultivating productive public-private partnerships between academia and industry.

During a recent interview in his office at USF Health, Dr. Bréchot talked about leading the Pasteur Institute, a preeminent global network of 33 institutes in 26 countries; his diverse background; and his new role at USF Health.  The interview has been edited for length.

What has been your area of research focus?

As an MD-PhD, I’ve always been convinced of the need to combine basic research with clinical practice — long before translational medicine became fashionable. My basic science research has combined cell biology and molecular virology, mostly focusing on hepatitis B (HBV) and hepatitis C (HCV) and how these viruses can induce liver cancer. I’ve also been very involved in developing diagnostic tests of HBV and HCV and evaluating new drugs to treat chronic forms of the infection.  More recently, I’ve worked on the mechanisms of liver regeneration and based on longstanding research activity in my laboratory, we discovered a new molecule (HIP/PAP, or hepatocarcinoma-intestine-pancreas/pancreatic associated protein), now being tested in clinical trials as a drug that may be useful for patients with a severe form of acute and chronic hepatitis. We’re contemplating organizing new phase 2 clinical trials in China, because China has so many people with chronic hepatitis B infection.

What were some major accomplishments at the Pasteur Institute under your leadership?

First, both at Inserm and the Pasteur Institute, I was very much focused on attracting and supporting young investigators. We created programs and special funding mechanisms to really give scientists at the early stages of their careers the means to develop interdisciplinary research and then get a grant. Second, at Pasteur, we reinforced research activities, especially in the fields of bioinformatics and integrative biology. We created a Center for Bioinformatics, Biostatistics and Integrative Biology (an international multidisciplinary center for processing, analyzing and modeling biological data) that included recruiting 40 high-level engineers and opening a new building.  Third, we merged the activities of different departments focused on the microbiota. For instance, we had a program called Brain and Microbes in which scientists working on infectious agents and those working in the neurosciences looked at how the bacteria of the intestine can modulate brain function, including disorders such as anxiety and depression.

What is the microbiome, and why is it such a hot area of research interest?

The microbiota is made up of populations of bacteria, fungi, certain viruses and other microorganisms present throughout the body.  It’s actually a very old topic:  The first microbiota intervention (to treat diarrhea) was done by a Chinese doctor 3,000 years before Christ (the ancient equivalent of a fecal microbiota transplant). What’s new is our technological progress – with the capacity for genome sequencing and advances in bioinformatics, we now have the possibility to investigate the human microbiota like never before… As a result, we’ve discovered very significant connections between dysbiosis — modifications of how microbe populations are distributed in the gut, the lungs, the skin — and metabolic disorders such as obesity and diabetes, cardiovascular diseases, neurological diseases like Parkinson’s and perhaps also Alzheimer’s, and some infectious diseases where disease severity correlates with what happens to intestinal bacteria. It’s a fascinating, challenging field with applications for cross-disciplinary research and translational medicine, and where international cooperation can be extremely interesting because the link between, say for example, the microbiota and diabetes may be very different in the U.S. and Africa due to the strong influence of environmental factors such as nutrition, as well as genetic variations… So, the science of microbiota as it affects certain diseases is a very good example of a collaboration which, if organized with centers in Africa, Southeast Asia and South America, could create a unique USF program very competitive with other universities.

What attracted you to the University of South Florida?

USF already has a lot of excellent ongoing research activities and in my discussions with senior leadership I found there’s real international ambition here, a desire and commitment to go further. I liked that.

What is your vision for helping advance research at USF Health?

I’m still in the stage where I need to listen and learn more about the research activities to see how I can best contribute. But, initially I want to work with Drs. Lockwood, (Paul) Sanberg, (Stephen) Liggett, (John) Sinnott and other leaders to delineate which strategic research areas need to be reinforced and then contribute to the high-level recruitment of scientists. Second, we’ll increase coordination among different departments working in research areas such as the intestinal microbiota and its impact on cardiovascular, neurodegenerative and infectious diseases. Third, I hope to contribute to the international expansion of USF, building upon the networks from my previous activities including work with industry partners.

I absolutely appreciate that I will only be efficient in helping to advance research activities at USF if I integrate into the team. It’s not always easy, but it works.

Dr. Bréchot will build on global networks from his previous activities, including work with industry partners.

You have said talent is key to research excellence. Is there one predominant quality you seek in selecting top talent?

You start by looking for bright minds. But, when you must choose among five scientists all with very bright minds, enthusiasm and the capacity to integrate are critically important. I’m a fan of soccer where you need to have very talented players, but you also very much need players with team spirit. Modern science needs researchers with an interdisciplinary mode of thinking who interact well with those from other disciplines.

Some things you may not know about Dr. Bréchot:

-Each generation of Dr. Bréchot’s family, dating back to King Louis XIV of France, had at least one medical doctor.

– As a student at Pasteur Institute, he helped set up the first diagnostic test to detect hepatitis B virus in blood; he also taught the first course in molecular biology in China in 1981.

-He met his wife Patrizia Paterlini Bréchot, MD, PhD, a professor of medicine at Necker School of Medicine and founder of a biotech company, when she came from Italy for a postdoctoral fellowship at Necker and Pasteur Institute in Paris. His five grown children include two MD-PhDs: a daughter who is a cancer immunologist at Pennsylvania State University, and a son who directs an intensive care unit at Pitié–Salpêtrière Hospital in Paris, one of Europe’s largest teaching hospitals. There are also six grandchildren, ranging from ages 1 to 11.

-Dr. Bréchot enjoys jogging, playing tennis and snow skiing. Currently, he’s reading about U.S. history, including biographies of George Washington and Abraham Lincoln.

-Photos by Eric Younghans, USF Health Communications and Marketing

USF Health’s cardiovascular team of faculty, researchers, doctors, nurses, physical therapists, pharmacists and public health professionals continue to develop top-quality research, education and state-of-the-art clinical care to make life better for patients suffering with heart disease. To learn more, click here.

Heart disease is the leading cause of death in the United States. According to American Heart Association (AHA), more than 6 million adults currently live with heart disease.

The number of people living with the condition is only expected to rise. AHA data shows that, by 2030, more than 8 million people could be diagnosed with heart disease.

The numbers are alarming. But, taking basic daily steps may help prevent or reduce heart disease and heart attack.

USF Health medical experts on cardiovascular disease weigh in – providing ten things people can do to keep their heart healthy. They suggest to:

Exercise daily

Vishal Parikh, MD, fellow of the Department of Cardiovascular Sciences at USF Health Morsani College of Medicine, says moderate exercise for at least 30 minutes a day can lower the risk of obesity, high blood pressure, high cholesterol and diabetes.

Quit smoking

Smoking increases the risk of heart disease and heart attack, says Amy Alman, PhD, assistant professor in the Department of Epidemiology and Biostatistics at the USF College of Public Health. “So, say no to smoking,” says Dr. Alman.

Maintain a healthy diet

“A bad diet can put a strain to your heart,” says Ponrathi Athilingam, PhD, assistant professor of cardiology at USF College of Nursing. She suggests considering healthy foods such as fruits, vegetables, whole grains, fish, poultry, lean meats, and nuts to help lower the risk of heart disease. She also recommends eating foods with low trans-fat, saturated fat or sodium.

Manage stress

Dr. Parikh says that stress adds strain to the heart. Constant stress causes behaviors that increase heart disease risks including smoking, excessive alcohol, physical inactivity and lack of sleep. So, he says, “It’s important for people to identify triggers and practice relaxing techniques such as meditation. Something just as simple as laughing may help combat stress.

Advanced genomic monitoring/testing

Kevin Sneed, PharmD, dean of the USF College of Pharmacy, said advanced genomic testing and monitoring, which provides an assessment of cardiovascular genes, helps detect any genetic abnormalities early. “This type of technology would provide awareness, and, most of all, give information for a more targeted intervention to prevent future complications,” says Dr. Sneed.

Maintain a balanced weight

Excessive weight gain increases the risk of cardiovascular disease. According to Center for Disease Control and Prevention, weight gain leads to high cholesterol, high blood pressure and diabetes. “To keep the body in check, remain physically active and, above all, consume whole foods rather than processed foods,” says Mary Soliman, PharmD, assistant professor at USF College of Pharmacy.

Get regular exams

USF Health cardiovascular experts suggest that having regular heart screenings is important – checking the heart rate, blood pressure, body fat and blood sugar. They believe regular screenings keep people informed, which ultimately help prevent heart disease.

Know family history  

Knowing about the family history is important. Having a relative or family member suffering from heart disease, greatly increases one’s risk. “If you have a family history of heart disease or a personal history of heart health risk factors (smoking, obesity, high blood pressure and cholesterol), you may just need to be more diligent in monitoring your heart health,” says Gregory M. Gutierrez, PhD, assistant professor at the USF Health School of Physical Therapy and Rehabilitation Sciences.

Maintain a healthy lifestyle

Keeping an overall healthy lifestyle is the secret to a healthy heart. USF Health experts all agree that lifestyle is key to lowering the risk of heart disease. Exercising, eating healthy, avoiding smoking and second hand-smoking and managing stress, lead to better heart health.

What women need to do

Heart disease causes, symptoms and outcomes may be different in women than in men, says Theresa Beckie, PhD, professor and cardiovascular health researcher at USF College of Nursing and Department of Cardiovascular Sciences in the USF Health Morsani College of Medicine. “Women represent a particularly high-risk phenotype. So, women, especially young women, need to pursue aggressive measures to reduce risks with daily physical activity, a healthy dietary pattern, and stress management,” says Dr. Beckie.

The founding director of the USF Health Heart Institute has a passion for innovation, translational medicine and entrepreneurship.

Samuel A. Wickline, MD, has parlayed his expertise in harnessing nanotechnology for molecular imaging and targeted treatments into an impressive $1-million portfolio of National Institutes of Health awards, multiple patents and four start-up biotechnology companies.

“We’ve developed nanostructures that can carry drugs or exist as therapeutic agents themselves against various types of inflammatory diseases, including, cancer, cardiovascular disease, arthritis and even infectious diseases like HIV,” said Dr. Wickline, who arrived at USF Health last month from the Washington University School of Medicine in St. Louis.

Dr. Wickline: “Innovation is not just about having a new idea, it’s about having a useful idea.”

 Dr. Wickline comments on how being a physician adds perspective to the science he conducts.

At Washington University, Dr. Wickline, a cardiologist, most recently was J. Russell Hornsby Professor in Biomedical Sciences and a professor of medicine with additional appointments in biomedical engineering, physics, and cell biology and physiology.

“I like the challenge of building things,” he said.

In St. Louis, he built a 29-year career as an accomplished physician-scientist keenly interested in translating basic science discoveries into practical applications to benefit patients. He served as chief of cardiology at Jewish Hospital, developed one of the first cardiac MRI training and research programs in the country, helped establish Washington University’s first graduate program in biomedical engineering, and led a university consortium that works with academic and industry partners to develop medical applications for nanotechnology.

At USF, there will be no shortage of challenging opportunities to build.

Building the USF Health Heart Institute

A major part of Dr. Wickline’s new job is helping to design, build and equip the Heart Institute. Most importantly, he will staff the state-of-the-art facility with a critical interdisciplinary mix of top biomedical scientists (including immunologists, molecular biologists, cell physiologists and genomics experts), who investigate the root causes of heart and vascular disease with the aim of finding new ways to detect, treat and prevent them. The Heart Institute will be co-located with new Morsani College of Medicine in downtown Tampa; construction on the combined facility is expected to begin later this year.

“I have been impressed by the energy and commitment here at the University of South Florida to invest substantial resources in a heart institute,” Dr. Wickline said. “I believe we have a lot to offer in terms of bench-to-bedside research that could solve some of the major cardiovascular problems” like atherosclerosis or heart failure.

“We want to put together a program that supplies the appropriate core facilities to attract the best and brightest researchers to this cardiovascular institute.”

Cardiovascular disease is the leading cause of death in the United States and worldwide, so exploring potential new treatment options is critical. One of the Heart Institute’s driving themes will be advancing concepts and findings that prove promising in the laboratory into projects commercialized for clinical use, Dr. Wickline said.

“Our goal is to make a difference in the lives of patients,” he said. “Innovation is not just about having a new idea, it’s about having a useful idea.”

Dr. Wickline also serves as associate dean for cardiovascular research and a professor of cardiovascular sciences at the Morsani College of Medicine. He holds the Tampa General Endowed Chair for Cardiovascular Research created last year with a gift from USF’s primary teaching hospital.

With Washington University colleague Hua Pan, PhD, a biomedical engineer and expert in molecular biology, Dr. Wickline is re-building his group at USF. Dr. Pan was recently recruited to USF as an assistant professor of medicine to continue her collaborations with Dr. Wickline.

 An example of Dr. Wickline’s group using nanotechnology to help combat atherosclerosis.

Dr. Wickline’s lab focuses on building nanoparticles to deliver drugs or other therapeutic agents to specific cell types, or targets.

Designing nanoparticles to “kill the messenger”

Dr. Wickline’s lab focuses on building nanoparticles – shaped like spheres or plates, but 10 to 50 times smaller than a red blood cell – to deliver drugs or other therapeutic agents through the bloodstream to specific cell types, or targets. These tiny carrier systems can effectively deliver a sizeable dosage directly to a targeted tissue, yet only require small amounts of the treatment in the circulation to reduce the risk of harmful side effects.

Some types of nanoparticles can carry image-enhancing agents that allow researchers to quantify where the illuminated particles travel, serving as beacons to specific molecules of interest, and enabling one to determine whether a therapeutic agent has penetrated its targeted site, Dr. Wickline said.

Dr. Wickline also is known for designing nanoparticles derived from a component of bee venom called melittin. While bee venom itself is toxic, Dr. Wickline’s laboratory has detoxified the molecule and modified its structure to produce a formula that allows the nanoparticles to carry small interfering (siRNA), also known as “silencing RNA,” or other types of synthetic DNA or RNA strand.

Among other functions, siRNA can be used to inhibit the genes that lead to the production of toxic proteins. Many in the nanotechnology research and development community are working to make siRNA treatment feasible as what Dr. Wickline calls “a message killer,” but the challenges have been daunting.

“The big challenge in the field of siRNA, and many companies have failed at this, is how to get the nanostructure to the cells so that the siRNA can do what it’s supposed – hit its target and kill the messenger — without being destroyed along the way, or having harmful side effects,” Dr. Wickline said. “We figured out how to engineer into a simple peptide all of the complex functionality that allows that to happen.”

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 Dr. Wickline comments on the underlying similarities between cardiovascular disease and cancer.

Different targets, same delivery vehicle

In a recent series of experiments in mice, Dr. Wickline and colleagues have shown that silencing RNA messages delivered by nanoparticle to a specific type of immune cell known as a macrophage – a “big eater” of fat – actually shrinks plaques that accumulate inside the walls of the arteries during atherosclerosis, one of the main causes of cardiovascular disease. The build-up of atherosclerotic plaques with fat-laden macrophages narrows, weakens and hardens arteries, eventually reducing the amount of oxygen-rich blood delivered to vital organs.

This type of plaque-inhibiting nanotherapy could be useful in aggressive forms of atherosclerosis where patients have intractable chest pain or after an acute heart attack or stroke to prevent a secondary cardiac event, Dr. Wickline said.

In another study, Washington University School of Medicine researchers investigated the potential of the siRNA nanoparticle designed by co-investigators Dr. Pan and Dr. Wickline in treating the inflammation that may lead to osteoarthritis, a degenerative joint disease that is a major cause of disability in the aging population. The nanoparticles — injected directly into injured joints in mice to suppress the activity of the molecule NF-κB — reduced local inflammation immediately following injury and reduced the destruction of cartilage. The findings were reported September 2016 in the Proceedings of the National Academy of Sciences.

Previously, Dr. Wickline said, the Washington University group had shown that nanoparticles delivered through the bloodstream inhibited inflammation in a mouse model of rheumatoid arthritis. And, another laboratory at the University of Kentucky is studying whether locally injected siRNA nanoparticles can quell the bacterial inflammation that can lead to a serious gum disease known as periodontitis. Other collaborating labs are using these nanoparticles in pancreatic, colon, and ovarian cancers with good effects.

“The specific targets in these cases may be different, but the nice thing about this kind of delivery system for RNA interference is that the delivery agent itself, the nanostructures, are the same,” Dr. Wickline said. “All we have to do is change out a little bit of the genetic material that targets the messages and we’re set up to go after another disease. So it’s completely modular and nontoxic.”

The St. Louis-based biotechnology company Trasir Therapeutics is developing these peptide-based nanocarriers for silencing RNA to treat diseases with multiple mechanisms of inflammation. Dr. Wickline co-founded the company in 2014 and continues to serve as its chief scientific officer.

Dr. Wickline with colleague Hua Pan, PhD, a biomedical engineer with expertise in molecular biology.

 Inhibiting chronic inflammation without getting rid of beneficial immune responses.

Calming the destructive cycle of inflammation

Dr. Wickline’s work is supported by several NIH RO1 grants, including one from the National Heart, Lung and Blood Institute to develop and test nanotherapies seeking to interrupt inflammatory signaling molecules and reduce the likelihood of thrombosis in acute cardiovascular syndromes.

In essence, Dr. Wickline said, he is interested in suppressing chronic inflammation, without disrupting the beneficial functions of surveillance by which the immune system recognizes and destroys invading pathogens or potential cancer cells.

“If you can inhibit the ongoing inflammation associated with (inappropriate) immune system response, you inhibit the positive feedback cycle of more inflammation, more plaques, more damage and more danger,” he said. “If you can cool off inflammation by using a message killer that says (to macrophages) ‘don’t come here, don’t eat fat, don’t make a blood clot’ – that’s what we think could be a game changer.”

Another NIH grant has funded collaborative work to develop an image-based nanoparticle that detects where in a compromised blood vessel too much blood clotting (hypercoagulation) occurs, and delivers potent anti-clotting agent only to that site. Formation of abnormal blood clots can trigger a heart attack when a clot blocks an artery that leads to heart muscle, or a stroke when a clot obstructs an artery supplying blood to the brain.

Because this site-specific nanotherapy targets only areas of active clotting, it may provide a safer, more effective approach against cardiac conditions like atrial fibrillation and acute heart attack than existing anticoagulant drugs such as warfarin and newer blood thinners like Xarelto® (rivaroxoban) or Eliquis® (apixiban), all which work systemically and come with raised risk for serious bleeding, Dr. Wickline said.

In a study published last year in the journal Arteriosclerosis, Thrombosis, and Vascular Biology, Dr. Wickline and colleagues found that nanoparticles delivering a potent inhibitor of thrombin, a coagulant protein in blood that plays a role in inflammation, not only reduced clotting risk but also rapidly healed blood vessel endothelial barriers damaged during plaque growth.

The preclinical work showed the experimental treatment “is actually an anti-atherosclerotic drug as well as an anti-clotting drug, so there are many potential applications,” Dr. Wickline said.

Dr. Wickline received his MD degree from the University of Hawaii School of Medicine. He completed a residency in internal medicine, followed by clinical and research fellowships in cardiology at Barnes Hospital and Washington University, where he joined the medical school faculty in 1987.

He has authored more than 300 peer-reviewed papers and holds numerous U.S. patents. Dr. Wickline is a fellow of the American College of Cardiology and the American Heart Association, and a 2014 recipient of the Washington University Chancellor’s Award for Innovation and Entrepreneurship.

– Photos by Sandra C. Roa and Eric Younghans

Tampa, FL (Dec. 20, 2016) — Samuel A. Wickline, MD, has joined the USF Health Morsani College of Medicine to lead a state-of-the-art heart institute that will integrate biomedical research with advanced clinical care to find new ways to detect, treat and prevent cardiovascular diseases and improve the heart health of the Tampa Bay community.

Dr. Wickline, a cardiologist, came to USF earlier this month from Washington University School of Medicine in St. Louis, where he was the J. Russell Hornsby Professor in Biomedical Sciences and a professor of medicine with additional appointments in biomedical engineering, physics, and cell biology and physiology.

As the first director of the USF Health Heart Institute, he will be instrumental in helping design, build, equip and staff the Heart Institute to be co-located with the new Morsani College of Medicine in downtown Tampa. Among his responsibilities will be the recruitment of a critical mass of cardiovascular scientists at the forefront of interdisciplinary biomedical research to define the root causes of heart and vascular disease leading to new diagnostics and treatments.

Samuel Wickline, MD, a cardiologist, is the USF Health Heart Institute’s first director. – Photo by Sandra C. Roa

Dr. Stephen Liggett, vice dean for research at the Morsani College of Medicine, and Dr. Arthur Labovitz, chair of the college’s Department of Cardiovascular Sciences, served as co-directors of the Heart Institute during its early planning and design phase.

“With a foundation firmly in place, we look forward to Dr. Wickline’s leadership in helping us build a world-class cardiovascular clinical and research program positioned to accelerate USF’s path to preeminence,” said Dr. Charles J. Lockwood, senior vice president for USF Health and dean of the Morsani College of Medicine.

Dr. Wickline will fill the Tampa General Hospital Endowed Chair for Cardiovascular Research, which was created earlier this year with a gift from USF’s primary teaching hospital.  He also holds appointments as associate dean for cardiovascular research and a professor of cardiovascular sciences at the Morsani College of Medicine.

“Heart disease is the number one killer of people in the world and the United States, and there are still innumerable problems to solve,” said Dr. Wickline, who is in the process of setting up his own laboratory at USF. “I have been impressed by the energy and commitment here at the University of South Florida to invest substantial resources in a heart institute… And from the perspective of what is done in the laboratory, I believe we have a lot to offer in terms of bench-to-bedside research that could solve some of the major cardiovascular problems.”

An accomplished physician-scientist with expertise in translating basic science discoveries into practical applications to benefit patients, Dr. Wickline will complement USF Health’s growing cardiology service, and brings to USF a longstanding National Institutes of Health grant portfolio of more than $1 million a year.  He studies the molecular basis of inflammation, cell death and atherosclerosis that cause heart, vascular and other organ diseases.

Much of Dr. Wickline’s pioneering research explores the molecular basis of disease-causing processes using novel imaging methods to detect the genetic signature of cells and deploying nanoparticles to treat a variety of cardiovascular conditions, including targeting atherosclerotic plaques that cause heart attacks. His academic entrepreneurial work has led to the development of advanced cardiac imaging techniques, such as magnetic resonance imaging of the heart to assess coronary artery disease.

Dr. Wickline earned his MD degree from the University of Hawaii School of Medicine, and completed his residency in internal medicine and fellowship in cardiology at Washington University School of Medicine, in St Louis.

During his career at Washington University, Dr. Wickline served as chief of cardiology at Jewish Hospital and helped establish the university’s first graduate program in biomedical engineering. He led a consortium that works with academic and industry partners to develop broad-based clinical applications for nanotechnology and imaging.  He also established the Siteman Center of Cancer Nanotechnology Excellence with National Institutes of Health funding.

Dr. Wickline has started four biotechnology companies, holds numerous patents, and has authored more than 300 peer-reviewed research papers.

-USF Health-
USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Physical Therapy and Rehabilitation Sciences, the Biomedical Sciences Graduate and Postdoctoral Programs, and the USF Physicians Group. USF Health is an integral part of the University of South Florida, a high-impact, global research university dedicated to student success. For more information, visit www.health.usf.edu

Media contact:
Anne DeLotto Baier, USF Health Communications
abaier@health.usf.edu or (813) 974-3303

Understanding the sensory nerves involved in protective behaviors may lead to new therapies for respiratory, cardiovascular diseases

Think about the last time you stubbed a toe.

The sensory nerves activated when your toe slammed against a hard object initiated a defensive reflex leading you to withdraw your toe from the source of intense pain. Tom Taylor-Clark, PhD, associate professor in the Department of Molecular Pharmacology and Physiology, likens the pain-induced response to an early warning system that, if working properly, helps us avoid things that can cause damage.

“If you stub your toe once, sure it hurts so much,” he said, “but if you do it repeatedly, eventually you will break your toe.”

In his laboratory at the USF Health Morsani College of Medicine, Dr. Taylor-Clark studies the role of defensive, or nociceptive, sensory nerves in health and disease. Using a combination of electrophysiology, imaging and molecular biology techniques, he investigates how these peripheral nerves, which stimulate organs and penetrate nearly all the body’s tissues, sense their environment. That includes sensory nerve response to external stimuli, like extreme heat or cold, inhaled pollutants or a source of injury, and internal stimuli, such as inflammation, infection or organ damage.

Thomas Taylor-Clark, PhD, an associate professor in the Department of Molecular Pharmacology and Physiology, studies the role of defensive, sensory nerves in health and disease.

“We are interested in understanding the sensory nerves involved in protective behaviors, or defense, because they are the ones that go wrong in disease and injury,” Dr. Taylor-Clark said.

The protective role of airway sensory nerves in cough

His laboratory focuses primarily on the electrical excitability of sensory nerves of the airways. The researchers study the behavior of sensory nerves connecting the lungs with the brainstem, the primitive part of the brain that controls basic body functions such as breathing, swallowing and heart rate. In particular, Dr. Taylor-Clark works with colleagues to better understand the nerves involved in initiating the chronic cough associated with the asthma, a disease characterized by persistent airway inflammation.

Knowing more about how these airway sensory nerves work, including the interface between the conscious and unconscious in the brainstem networks that control cough, is important in understanding how they are disrupted by inflammatory disease. The information could help guide the design of new treatments for unresolved cough and associated symptoms, a major reason people visit primary care providers, Dr. Taylor-Clark said. In addition, better ways to treat cough are important, because for those with a variety of neuromuscular diseases impaired cough can cause an increase in pulmonary infections from aspiration.

Recently, Dr. Taylor-Clark’s team expanded their research to look into how pre-existing cardiovascular disease alters nerve-generated reflexes from the lungs to affect cardiovascular function.

 Dr. Taylor-Clark comments on one aspect of his laboratory’s sensory nerve research.

Stephen Hadley, a senior biological scientist in Dr. Taylor-Clark’s laboratory.

Three research awards totaling more than $2.85 million support their work. The studies are done using cell cultures as well as with the help of transgenic mice that selectively express red fluorescent protein in defensive neurons.

With a grant from the National Heart, Blood and Lung Institute, Dr. Taylor-Clark has investigated the connection between two well-known research findings to determine the downstream effects of mitochondria, the energy producers of the cell, on airway sensory nerve activation. The first finding, he said, was that airway sensory nerves respond to a type of inflammatory signaling that induces potentially damaging oxidative stress. The second was that mitochondria are located right next to signaling receptors in the sensory nerve cells.

“So, we hypothesized that perhaps mitochondria are not there just to produce energy, but to generate signaling,” Dr. Taylor-Clark said. “And we found that mitochondrial signaling activates the sensory nerves specifically by activating chili and wasabi receptors in airways.”

Hot on the trail of wasabi and chili receptors

These receptors for chili peppers (or capsaicin) and wasabi (allylisothiocyanate), officially known as TRPV1 and TRPA1 respectively, are expressed by every single defensive sensory nerve in your body, including those in your tongue, your skin – and your airways (nasal passages, bronchi, larynx). Together the TRPV1 and TRPA1 compounds contribute to involuntary cough reflex.

The USF work linking mitochondrial signaling and airway sensory nerve receptors, triggered by these TRPV1 and TRPA1 molecules that can generate pain as well as heat sensation, resulted in two major papers in the journal Molecular Pharmacology, one in 2013 and another in 2014. A supplementary biophysiological study defining how the wasabi (TRPA1) receptor works was published earlier this year in the Journal of General Physiology.

Above and below: Microscopic images from a transgenic mouse expressing the red fluorescent protein tdTomato  in defensive sensory nerve only.  This crosssection of the lung showing defensive nerve terminals (red)  innervating regions surrounding the small branches of bronchiles, or air tubes (green), within the lungs.

A slice of the brainstem showing central projections of defensive nerves (red) into the medulla, where the nerves transmit signals to brainstem networks to control various involuntary functions like breathing, cough, swallowing, heart rate and blood pressure.

Pollution-induced exacerbation of underlying cardiovascular disease

Another direction of scientific endeavor for Dr. Taylor-Clark is investigating how pre-existing cardiovascular disease may alter normal reflexes from the lungs to affect autonomic regulatory control of the heart. Seed funding from an earlier Morsani College of Medicine Research Office intramural BOOST grant helped his research group obtain a two-year American Heart Association award for this more recent area of research under the auspices of the USF Health Heart Institute.

In preliminary research presented last year at the Experimental Biology Conference, Dr. Taylor-Clark and colleagues reported that hypertensive rats exposed to wasabi, an irritant mimicking the effects of a pollutant like ozone when inhaled into the lungs, experience a much different cardiac response than healthy rats. The heart rate of healthy rats exposed to wasabi slows significantly as a protective mechanism to help slow the distribution of pollutants throughout the body. But given the same exposure, rats with chronic high blood pressure have periods of rapid heartbeats interspersed with a slow heart rate – which can evoke a potentially dangerous abnormal heart rhythm known as premature ventricular contractions.

“So you have a situation where you’ve gone from a healthy (cardiovascular) reflex to an aberrant reflex that may exacerbate pre-existing cardiovascular disease,” he said.

Working with researchers at the University of Florida, Dr. Taylor-Clark is a co-investigator for a recently awarded a three-year, $1.28M grant from the National Institutes of Health Common Fund’s Stimulating Peripheral Activity to Relieve Conditions (SPARC) funding program. The comprehensive project aims to improve maps of the peripheral nervous system —the electrical wiring that connects the brain and spinal cord with the rest of the body – so that more selective and minimally invasive “electroceutical” treatments might be developed for conditions such as heart disease, asthma and gastrointestinal disorders.

 USF’s involvement in NIH project charting defensive airway nerves.

Dr. Taylor-Clark and Stephen Hadley. Recently, Dr. Taylor-Clark’s laboratory expanded its research to look into how pre-existing cardiovascular disease alters nerve-generated reflexes from the lungs to affect cardiovascular function.

Mapping for the future of neuromodulation therapies

The UF-USF multidisciplinary team is focusing on functional mapping of peripheral and central neural circuits for airway protection and breathing.

Using cutting-edge genetic and neurophysiological approaches, they are characterizing the types of defensive airway nerves that control breathing, coughing and heart rate differently and finding where they connect into the brainstem network.

“We are trying to bridge the gap between what has been done (with nerve trafficking) in the lungs and what has been done in the brainstem, and then link them together,” Dr. Taylor-Clark said. “We have transgenic mice that make red fluorescent protein only in their defensive nerves, so now we can chart where targeted nerves are going with superior image quality.”

The team’s overall goal is to advance understanding of the neural pathways underlying respiratory control, laying the groundwork for future neuromodulation therapies to normalize lung function in people at risk.

“If we want to (preferentially) target these therapies for optimal effectiveness, we need to know where all these nerves go and what they do,” Dr. Taylor-Clark said.

Dr. Taylor Clark-received his PhD degree from University College London in 2004. He completed a postdoctoral fellowship at Johns Hopkins University Division of Allergy and Clinical Immunology and served as a medical faculty member at Hopkins for a year before joining USF’s medical school in 2009 as an assistant professor.

Dr. Taylor-Clark is associate chair for research in the Department of Molecular Pharmacology and Physiology. In 2015, he received the Award for Excellence in Teaching from USF’s Graduate PhD Program in Integrated Biological Sciences.

 How mapping neural circuits for airway protection and breathing may lead to novel therapies.

A combination of electrophysiology, imaging and molecular biology techniques are used to study behavior of sensory nerves connecting the lungs with the brainstem.

Some things you might not know about Dr. Taylor-Clark:

• In the mid-1990s, for two years before entering University College London as an undergraduate, he played bass guitar in a band that recorded and performed “very loud rock and roll” as part of the London music scene. These days, with wife Luciana as the audience, Dr. Taylor-Clark jams at home in his living room with daughter Ella, 9, who plays drums.

• Taylor-Clark’s PhD thesis involved a study of how the human nose congests. He measured the internal dimensions of people’s nasal passages with a sonar device at the end of a stick, recruiting family and friends, among others, as study volunteers. He induced sneezing and other symptoms of hay fever by spraying histamine into their nostrils. The shape of the nose and the interaction between nerves and blood vessels in the nose affected air flow and severity of symptoms, he discovered. “While writing the thesis, I began to realize how little was understood about nerves in the airways.”

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 Photos by Eric Younghans, USF Health Communications