Peter C. Gazes Cardiac Research Institute

Research Profile

My laboratory is focused on the analysis of signaling and gene regulatory pathways, which play a role in cardiac failure. Recently, we have demonstrated that protein acetylation, regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) plays a significant role in modulating gene expression in cardiac pathologies. Importantly, treatment with HDAC inhibitors preserves ventricular remodeling and cardiac function in pre-clinical models of cardiac hypertrophy, myocardial infarction (MI), ischemia reperfusion (IR) and heart failure. We have determined that HDAC inhibitors promote the polarization of inflammatory M1 macrophages to anti-inflammatory M2 macrophages, resulting in reduced deleterious remodeling and preserve cardiac function in the post MI heart.

Our study is the first account of the benefit of HDAC inhibition being due in part to its ability to polarize macrophages, a cellular component underappreciated until recently in cardiac pathologies. Our work has also identified a mechanism that has served as a paradigm of how HDACs can mediate both repression and activation of gene expression. We have also identified an important mechanism whereby HDAC inhibitors can repress cardiac gene expression by altering the acetylation state of co-activator and co-repressors of transcription. We have also shown that the acetylation state of specific transcription factors affects their interaction with co-activators and co-repressors. Therefore, HDACs can facilitate gene activation via the direct deacetylation of transcription factors allowing for recruitment of co-activators to the promoter. Our overall goal is to translate our basic and pre-clinical discoveries into important new therapies for patients with heart disease.

Dr. Prins is a Professor of Medicine in the Division of Cardiology and Director of the Gazes Cardiac Research Institute at MUSC. He trained at the University of Alabama-Birmingham and then completed an integrated research and clinical cardiology fellowship at the University of Minnesota. He also runs a NIH-funded laboratory aimed at understanding and treating right heart failure and pulmonary hypertension.

Dr. Prins cares for patients with multiple cardiovascular diseases. He is particularly interested in right heart failure, tricuspid regurgitation, dyspnea, and pulmonary hypertension.

Research Profile

My long-standing research interest is in the area of cardiac biomechanics. Specifically, the contractile and viscoelastic mechanical properties of cardiac biomaterials represent the focus and commitment of my research efforts. In the Zile laboratory, we perform multiple experimental studies in small and large animal models of cardiac disease, especially cardiac hypertrophy and heart failure induced by pressure overload. We continue to work closely with many collaborating investigators to evaluate various indices of cardiovascular function in our animal models of heart disease. My mentor, Michael Zile, M.D., and I closely collaborate on multiple basic, translational, and clinical research projects to define the extracellular molecular mechanisms that cause the development of myocardial remodeling, diastolic dysfunction, and chronic heart failure.

Our research laboratory has been supported by grants from the National Heart, Lung and Blood Institute, American Heart Association, Medical University of South Carolina, National Aeronautics and Space Administration, US Department of Veterans Affairs, and US Department of Defense.

Research Profile

The Bradshaw laboratory is focused on cellular mechanisms controlling procollagen processing and collagen deposition in cardiac fibrosis and in periodontal ligament repair.

A fundamental question in cell biology is how cells regulate the synthesis and construction of tissue-specific extracellular matrices (ECMs) in their environment and, in turn, how changes in the structure and composition of the ECM can influence cell behavior in response to injury and disease. In particular, we are interested in cellular mechanisms of collagen fibril assembly in the ECM and the function of matricellular proteins in the regulation of this process. Matricellular proteins are defined as proteins that associate with the ECM but do not contribute structurally to the ECM in contrast to classical ECM proteins such as collagen and laminin. We have established that one matricellular protein, SPARC (secreted protein acidic and rich in cysteine, osteonectin, BM-40), influences the formation of collagen I fibers in connective tissues of mice. For example, collagen accumulation associated with cardiac pressure-overload hypertrophy is significantly reduced in SPARC-null mice. Elucidation of pathways by which SPARC and other collagen binding proteins influence collagen incorporation and stability in the ECM can lead to the design of strategies to control fibrotic processes in the heart and in other tissues. Alternatively, in diseases in which collagenous tissue is degraded, such as in periodontal disease, factors that improve collagen assembly could be used as essential tools to restore damaged tissues.

Recently, my laboratory defined a novel role of SPARC in regulating the activity of transglutaminase in collagen fibril assembly. We reported that inhibition of transglutaminase activity altered collagen content, fibril diameter, and mechanical properties of tissue. As transglutaminase is highly expressed by macrophages, an interesting speculation is functional differences in collagen deposition might be tightly regulated by macrophage expression of transglutaminase and SPARC thus contributing to the disorganized fibrotic deposition of collagen in disease. The Bradshaw laboratory has been supported by grants from the National Heart, Lung and Blood Institute, the American Heart Association, the Medical University of South Carolina, and the US Department of Veterans Affairs.

Dr. DeLeon-Pennell was trained in cardiovascular sciences at Baylor University, University of Texas Health Science Center San Antonio, and the University of Mississippi Medical Center.  She has >10 years’ experience with all aspects of the inflammatory and fibrotic components of cardiac remodeling following a heart attack. Her current research projects focus on the role of the adaptive immune system and how it interplay with the innate immune system to regulate cardiac wound healing. This includes evaluating how existing confounding variables such as gender or aging changes these processes.

Research Profile

The DeLeon-Pennell Lab focuses on all aspects of the inflammatory and fibrotic components of cardiac remodeling following a heart attack (myocardial infarction; MI). This includes evaluating how existing variables such as gender or aging changes these processes. Our major research focus is on the role of the adaptive immune system and the interplay with the innate immune system to regulate cardiac wound healing. These changes include cell-cell and cell-matrix interactions, which both affect and react to processes involved in tissue repair.

Overall our goal is to:

1. Develop multidimensional approaches to examine the mechanisms whereby the innate and adaptive immune system influences cardiovascular remodeling
2. Understand the dynamics and function of bio-molecules involved in cardiac remodeling
3. Improve current therapeutic strategies to prevent, slow, or reverse the progression to heart failure

Recently our lab has identified new mechanisms implicating CD8+ T-cells as regulators of the post-MI wound healing process. Our data indicated without functional CD8+ T-cells there was a decrease in left ventricular dilation and improved mortality post MI. In addition CD8+ T-cells were found to facilitate removal of necrotic tissue and the development of the fibrotic scar. The DeLeon-Pennell laboratory has been supported by grants from the National Heart, Lung and Blood Institute, the American Heart Association, the Medical University of South Carolina, and the US Department of Veterans Affairs.

Research Profile 

Dr. del Monte’s lab focuses on basic cardiac muscle pathophysiology and translational research to understand the pathogenesis of cardiomyopathies and heart failure (HF) as an Alzheimer’s disease and for the discovery of novel therapies. The lab utilizes an interdisciplinary approach in-vitro and in-vivo physiology, molecular biology and imaging as well as biophysical and structural-chemistry approaches. The early work from Dr. del Monte’s lab focused on Ca2+ homeostasis in the failing heart and gene therapy. For those studies, Dr. del Monte is a recognized leader in cardiomyocytes physiology and Ca2+ handling in animal models and human hearts. Dr. del Monte’s research has evolved towards cutting edge and innovative unexplored territories linking Alzheimer’s Disease and heart failure. The latest discoveries are recognized as a major breakthrough that opened a new era for the understanding of the pathogenesis of HF.

Dr. del Monte discovered, in dilated cardiomyopathy (iDCM), plaque and tangles-like protein aggregates similar to the pathological defects in Alzheimer Disease (AD). Since this first discovery the lab determined that Alzheimers Disease and cardiomyopathy share the same pathogenic defect changing the paradigm of the pathogenesis of iDCM. The lab characterized the cell response to misfolded proteins; identified genetic variants in common between iDCM and AD; purified and chemical characterized the composition of amyloid fibrils of cardiac plaques identifying an actin-polymerizing protein-Cofilin-2 to be comprised within the aggregates and characterized its role on cardiac function; identified how misfolded proteins exert their toxic effect and developed the new concept of metastatic transmissibility of pre-amyloid oligomers.

In addition to identifying Alzheimer’s like plaques and tangles in the heart of patients with cardiomyopathy the lab determined that the heart of patients with primary diagnosis of Alzheimer’s contains Ab deposits and present diastolic dysfunction. Given the commonality of the structure/function of misfolded proteins, the results obtained on cardiomyocytes can be translated to any cell, and studying the heart can provide insights for the detection of onset and progression of brain disorders using the heart as a window to the brain and offering a common therapeutic target for diseases affecting millions of people. Supporting activities for the cardiology division are mentoring students and fellows, from experience as reviewer for K08, K99-R00, R01 NIH grants. Dr. del Monte is also the Director of the human hearts biorepository at MUSC.

Dr. Zile is a graduate of Rush University School of Medicine. He did his internal medicine residency at Rush Presbyterian St. Lukes Medical Center in Chicago, a clinical cardiology fellowship at Tufts-New England Medical Center in Boston and a research cardiology fellowship at the Department of Veterans Affairs Medical Center, Boston.

Dr. Zile is currently the Charles Ezra Daniel professor of medicine at the Medical University of South Carolina. He also serves as the director of cardiology at the Ralph H. Johnson Department of Veteran's Affairs Medical Center in Charleston. He is an adjunct professor of bioengineering at Clemson University.

Dr. Zile's research career has involved both basic laboratory research examining the mechanisms of disease development and progression and translational clinical research examining the application of these basic mechanisms to development of effective treatment methods.

Dr. Zile is a recognized leader in the areas of cardiac function, congestive heart failure, diastolic heart failure and valvular heart disease. His research is supported by grants from the National Heart, Lung and Blood Institute, the American Heart Association, the Department of Veterans Affairs and the Medical University of South Carolina.

Dr. Zile is the author of over 100 peer-reviewed publications. He is a member of a number of professional societies including the American College of Physicians, American Federation of Clinical Research, American Heart Association, American College of Cardiology, the Heart Failure Society of America, International Society of Heart Failure, and the American Physiology Society. Dr. Zile has served on the research, educational and program committees of these organizations. He serves on the editorial boards of the Journal of the American College of Cardiology and Circulation and is an editorial consultant to a number of others including Circulation Research, Journal of Clinical Investigation and the American Journal of Physiology. Dr. Zile is a member of the Association of University Cardiologists and a member of the ABIM Subspecialty Board on Cardiovascular Disease.

Research Profile

Effective management of patients with chronic heart failure (CHF) remains one of the most critical unmet needs in cardiology in the United States and in the world. The fundamental goals of our research efforts over the last 35 years have been to define the ventricular, myocardial, cellular, and molecular mechanisms that cause the development and the progression of CHF and then to use these identified mechanisms as targets to improve diagnostic techniques, prognostic prediction, and therapeutic management of patients with CHF. In particular, I have focused my efforts on the clinical syndrome of heart failure (HF) with a preserved ejection fraction (HFpEF). More than 50% of all HF patients have HFpEF. HFpEF results in morbidity and mortality rates that are staggering: 50 to 60% 5-year mortality rate, 50% 6-month rehospitalization rate, and severe clinical disability. However, as stated in the current HF guidelines: “to date, no treatment management strategies have yet been shown, convincingly, to reduce morbidity or mortality in patients with HFpEF”.

Together with collaborators, we have developed state-of-the-art imaging techniques to characterize the structural and functional remodeling that occur in CHF patients. In addition, we have applied these techniques in an echocardiographic core laboratory used for all of our clinical, translational, and basic science studies. We have also developed clinically relevant animal models of human disease, state-of-the-art methods to assess cardiovascular remodeling, extracellular matrix homeostasis and myocardial function, and applied innovative advanced progenitor cell, transgenic and viral-based alterations in gene expression, translation, and activity to define the pathophysiologic mechanisms underlying CHF.

The Zile laboratory has been supported by research grants from the National Heart, Lung and Blood Institute, the American Heart Association, the Medical University of South Carolina, the National Aeronautics and Space Administration, the United States Department of Veterans Affairs, the United States Department of Defense.