Heart disease is a leading cause of death worldwide. But significant disparities exist in the incidence and severity of heart disease, particularly between men and women, and major barriers remain for the successful long-term care of heart disease patients. Now, thanks to a $12-million Program Project Grant (PPG) from the National Heart, Lung, and Blood Institute, scientists at the Lewis Katz School of Medicine at Temple University (LKSOM) are set to break down these barriers by exploring molecular mechanisms of heart injury and repair. Ultimately, they hope to identify new paths to the development of innovative heart therapies.

The Principal Investigator on the new award is Walter J. Koch, PhD, W.W. Smith Endowed Chair in Cardiovascular Medicine, Professor and Chair of the Department of Pharmacology, and Director of the Center for Translational Medicine at LKSOM. “We are very excited about the new PPG,” Dr. Koch said. “It gives us an exciting opportunity to discover more about the molecular basis of heart disease and, more specifically, heart failure, which affects more than six million people in the United States alone.”

Advances in treatments for heart disease over the course of the last decade have significantly improved patient survival. But mortality from heart failure, a major form of heart disease, remains high – about 40 percent of heart failure patients die within five years of diagnosis. In addition, little is known about why men experience more rapid heart failure progression than women.

“The persistently high rate of mortality in heart failure has created a significant need to learn more about mechanisms underlying tissue injury and tissue repair processes in the heart,” Dr. Koch said.

To explore these aspects of heart disease, Dr. Koch and Center for Translational Medicine colleagues Raj Kishore, PhD, Professor of Pharmacology and Medicine and Director of the Center's Stem Cell Therapy Program; Douglas Tilley, PhD, Associate Professor of Pharmacology; and John Elrod, PhD, Associate Professor of Pharmacology and Associate Professor at the Alzheimer's Center at Temple, designed four distinct yet complementary and highly collaborative projects.

Dr. Koch's team will examine the role of molecules known as G protein-coupled receptor kinases (GRKs) in heart function and disease. Part of this project is aimed at identifying the role specifically of GRK5 in heart failure. The team will also investigate whether limiting GRK5 activity can reduce tissue remodeling that occurs in the failing heart.

Dr. Kishore's portion of the research is focused on understanding the influence of gender on the ability of bone marrow stem cells to repair heart tissue. In particular, his team will test the hypothesis that female-derived stem cells possess superior reparative properties compared to their male counterparts and that functional superiority of female stem cells involves both hormone-dependent and hormone-independent mechanisms.

“Whether there is a gender basis for differences in stem cell function in the repair of the injured heart – particularly a molecular basis for superior functionality of female-derived stem cells – is not known,” Dr. Kishore said.

The third project, headed by Dr. Tilley, will explore the development of renal dysfunction during heart failure. “Renal dysfunction, in the form of cardiorenal syndrome (CRS), is a predictor for poor prognosis in heart failure patients,” Dr. Tilley said. “A key indicator of CRS is renal fibrosis, which impairs proper kidney function, and prevention of which may help ameliorate heart failure.”

Dr. Tilley and colleagues aim to define the role of immune cells known as leukocytes in mediating renal fibrosis in heart failure. Leukocytes regulate tissue fibrosis and are recruited to the kidney in various disease states. Working with co-investigator Meredith Brisco-Bacik, MD, MSCE, FACC, Associate Professor of Medicine and Clinical Sciences at LKSOM, Dr. Tilley's team will further examine molecular profiles of leukocytes collected from the blood of patients with or without CRS.

“We are excited to work with Drs. Koch, Kishore, and Elrod to examine facets of leukocyte biology, including alterations in leukocyte-specific GRK expression and signaling, sex-based differences in leukocyte behavior, and alterations in leukocyte bioenergetics, to determine their impact on CRS progression and outcomes,” Dr. Tilley added.

Dr. Elrod will lead the fourth project, which follows on his laboratory's discovery that targeting the process of calcium exchange in mitochondria (the energy-supplying powerhouses of cells) is an effective strategy to reduce tissue injury associated with heart attack. His team is especially interested in understanding the role of a molecule known as MCUB in the regulation of mitochondrial calcium transport in heart failure. These studies could uncover ways to therapeutically reduce mitochondrial dysfunction in heart tissue.

The new award, completely housed in the Center for Translational Medicine at Temple, also funds one administrative and two scientific cores, one directed by Dr. Koch and the others led by Erhe Gao, MD, PhD, Professor in the Center for Translational Medicine and Sudarsan Rajan, PhD, Assistant Professor in the Center.

“This award is a testament to what we have built here at Temple and the Center for Translational Medicine under Dr. Koch’s impeccable leadership,” Dr. Kishore noted. “The scientific depth of these multi-component studies is quite exciting and is likely to open up new understanding of and potentially new therapeutic avenues for heart disease.”

“Historically, a department or center that is funded by the PPG mechanism has been viewed as preeminent in their field and highly successful,” Dr. Elrod added. “The fact that this is the second currently funded PPG emanating from the Center for Translational Medicine speaks volumes to the collaborative nature and scientific impact of our group as a whole.”

Editor’s Note: The content above is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Image Description: This image shows heart sections from mice that are four weeks post-heart attack (myocardial infarction) that are in heart failure  – one is a normal mouse (left) and the other is mice with elevated levels of an enzyme known as GRK5 (right). This enzyme is also higher in patients with heart failure. These heart muscle sections are histologically stained with Masson’s trichrome to identify fibrosis which is replacement of viable heart cells with collagen. You can see that the hearts with elevated GRK5 have much more fibrosis and they do much worse after a heart attack than normal mice with normal levels of this enzyme.