(Philadelphia, PA) - The inability of cells to eliminate damaged proteins and organelles following the blockage of a coronary artery and its subsequent re-opening with angioplasty or medications - a sequence known as ischemia/reperfusion - often results in irreparable damage to the heart muscle. To date, attempts to prevent this damage in humans have been unsuccessful. According to a new study by scientists at the Lewis Katz School of Medicine at Temple University (LKSOM), however, it may be possible to substantially limit reperfusion injury by increasing the expression of a protein known as Bcl-2-associated athanogene 3 (BAG3).
"We found that BAG3 plays a pivotal role in protecting the heart from damage caused by reperfusion injury," explained the study's lead author, Feifei Su, MD, PhD, a postdoctoral fellow in the laboratory of Arthur M. Feldman, MD, PhD, Professor of Medicine at LKSOM.
Ischemia impairs the function of cellular organelles including mitochondria, the cell's energy-producers, resulting in harmful effects that set the stage for a sudden burst in the generation of toxic oxidizing substances when oxygenated blood reenters the heart. The toxins lead to fundamental changes in the biology of the heart. Notably, they activate cell death pathways and decrease autophagy - the process by which cells remove malfunctioning proteins and organelles. Autophagy plays a critical role in removing damaged myocardial cells (the muscular tissue of the heart) and misfolded heart muscle fibers.
The new work shows that BAG3 expression both inactivates cell death pathways, helping prevent the loss of heart cells triggered by ischemia, and activates autophagy, thereby enabling cells to clear out impaired components of the heart cell before they inflict extensive damage. The findings, published online November 17 in the journal JCI Insight, open the door to the investigation of BAG3 as a therapeutic target during reperfusion in heart attack patients.
In initial work, the research group found that BAG3 promotes autophagy and inhibits programmed cell death (apoptosis) in cultured cardiac myocytes. Subsequently, they found that when heart cells were exposed to the stress of hypoxia/reoxygenation or when living mice were stressed with ischemia/reperfusion, they suffered dramatic reductions in BAG3 expression.
Those paradoxical changes in BAG3 levels turned out to be directly associated with increases in biomarkers of autophagy and with decreases in biomarkers of apoptosis. By artificially knocking down BAG3 in mouse heart cells, the researchers were able to produce an apoptosis-autophagy biomarker phenotype nearly identical to that produced by hypoxia/reoxygenation. By contrast, BAG3 overexpression normalized apoptosis and autophagy.
In a key experiment, the Temple team further showed that tissue damage sustained following ischemia/reperfusion could be substantially reduced by treating mice with BAG3 prior to vessel re-opening. BAG3 overexpression before the onset of ischemia/reperfusion also resulted in normalization in apoptosis and autophagy biomarkers.
According to Dr. Feldman, the senior investigator on the project, his team's interest in the role of BAG3 in the heart has grown in recent years, owing to their discovery of a unique BAG3 mutation in a family with familial dilated cardiomyopathy, a genetic condition characterized by the development of heart failure between early and late adulthood.
"After finding that a mutation in BAG3 caused heart failure in a Philadelphia family, we have been trying to figure out what the protein does in the heart," Dr. Feldman said. "Now that we have a better understanding of its role and what happens when its levels are increased, we can investigate the possibility of targeting BAG3 in human patients using gene therapy or a small molecule."
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Other researchers on the new study include Feifei Su in the Department of Medicine at LKSOM, Temple University, and the Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China; Valerie D. Myers in the Department of Medicine at LKSOM, Temple University; Tijana Knezevic, Farzaneh G. Tahrir, Manish K. Gupta, Jennifer Gordon, and Kamel Khalili in the Department of Neuroscience at LKSOM, Temple University; JuFang Wang, Ehre Gao, Muniswamy Madesh, Joseph Rabinowitz, Douglas G. Tilley, and Joseph Y. Cheung in the Center for Translational Medicine at LKSOM, Temple University; and Frederick V. Ramsey in the Department of Clinical Sciences at LKSOM, Temple University.
The research was supported by National Institutes of Health grants P01 HL 091799-01 and R01 HL123093.
About Temple Health
Temple University Health System (TUHS) is a $1.6 billion academic health system dedicated to providing access to quality patient care and supporting excellence in medical education and research. The Health System consists of Temple University Hospital (TUH), ranked among the "Best Hospitals" in the region by U.S. News & World Report; TUH-Episcopal Campus; TUH-Northeastern Campus; Fox Chase Cancer Center, an NCI-designated comprehensive cancer center; Jeanes Hospital, a community-based hospital offering medical, surgical and emergency services; Temple Transport Team, a ground and air-ambulance company; and Temple Physicians, Inc., a network of community-based specialty and primary-care physician practices. TUHS is affiliated with the Lewis Katz School of Medicine at Temple University.
The Lewis Katz School of Medicine (LKSOM), established in 1901, is one of the nation's leading medical schools. Each year, the School of Medicine educates approximately 840 medical students and 140 graduate students. Based on its level of funding from the National Institutes of Health, the Katz School of Medicine is the second-highest ranked medical school in Philadelphia and the third-highest in the Commonwealth of Pennsylvania. According to U.S. News & World Report, LKSOM is among the top 10 most applied-to medical schools in the nation.
Temple Health refers to the health, education and research activities carried out by the affiliates of Temple University Health System (TUHS) and by the Katz School of Medicine. TUHS neither provides nor controls the provision of health care. All health care is provided by its member organizations or independent health care providers affiliated with TUHS member organizations. Each TUHS member organization is owned and operated pursuant to its governing documents.
Journal
JCI Insight