Cardiac myocytes die by apoptosis during ischemia-reperfusion injury and heart failure. A body of work from the Pl's lab and others has demonstrated that inhibition of this cell death through pharmacologic or genetic means decreases myocardial damage, limits left ventricular dilation, improves contractile function, and in some cases, decreases mortality. These studies provide the initial """"""""proof of concept"""""""" that cardiac myocyte apoptosis is an important pathogenic mechanism for ischemia-reperfusion injury and heart failure and suggest that inhibition of cell death may provide a novel therapeutic target for these disorders. We now wish to focus our attention on the molecular regulation of apoptosis specifically in cardiac myocytes. The central death machinery has been highly conserved from worm to human and differs little among various cell types. Despite this, apoptosis is often regulated in a cell type- and stimulus-specific manner, the basis of which is poorly understood. ARC (Apoptosis Repressor with a CARD (caspase recruitment domain)) is an endogenous inhibitor of apoptosis that is expressed primarily in cardiac and skeletal muscle. It is the only cardiac-enriched apoptosis regulatory molecule identified to date. ARC's importance is underscored by its potent inhibition of cardiac myocyte apoptosis elicited by diverse stimuli. Little is known, however, about ARC's mechanism of action, regulation, and in vivo effects. We will begin to define these areas through the following aims: 1. To determine the mechanism of ARC's novel interactions with and regulation of the apoptotic DNA degradation machinery. 2. To determine the mechanism of ARC degradation during apoptosis. 3. To determine whether persistent myocardial expression of ARC in vivo attenuates acute and chronic abnormalities in cardiac structure and function due to ischemia-reperfusion injury. Taken together, these studies will deepen our mechanistic and physiological understanding of ARC. This information may provide the basis for strategies to exploit this cardiac-enriched endogenous inhibitor to design novel and specific therapies for ischemic heart disease and heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Evans, Frank
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Moslehi, Javid; Amgalan, Dulguun; Kitsis, Richard N (2017) Grounding Cardio-Oncology in Basic and Clinical Science. Circulation 136:3-5
McKimpson, Wendy M; Zheng, Min; Chua, Streamson C et al. (2017) ARC is essential for maintaining pancreatic islet structure and ?-cell viability during type 2 diabetes. Sci Rep 7:7019
Mera, Paula; Laue, Kathrin; Ferron, Mathieu et al. (2016) Osteocalcin Signaling in Myofibers Is Necessary and Sufficient for Optimum Adaptation to Exercise. Cell Metab 23:1078-1092
Maejima, Yasuhiro; Chen, Yun; Isobe, Mitsuaki et al. (2015) Recent progress in research on molecular mechanisms of autophagy in the heart. Am J Physiol Heart Circ Physiol 308:H259-68
Yuan, Chujun; Yan, Lin; Solanki, Pallavi et al. (2015) Blockade of EMAP II protects cardiac function after chronic myocardial infarction by inducing angiogenesis. J Mol Cell Cardiol 79:224-31
McKimpson, Wendy M; Yuan, Ziqiang; Zheng, Min et al. (2015) The Cell Death Inhibitor ARC Is Induced in a Tissue-Specific Manner by Deletion of the Tumor Suppressor Gene Men1, but Not Required for Tumor Development and Growth. PLoS One 10:e0145792
Dorn 2nd, Gerald W; Kitsis, Richard N (2015) The mitochondrial dynamism-mitophagy-cell death interactome: multiple roles performed by members of a mitochondrial molecular ensemble. Circ Res 116:167-82
Kung, G; Dai, P; Deng, L et al. (2014) A novel role for the apoptosis inhibitor ARC in suppressing TNF?-induced regulated necrosis. Cell Death Differ 21:634-44
Park, Misun; Vatner, Stephen F; Yan, Lin et al. (2013) Novel mechanisms for caspase inhibition protecting cardiac function with chronic pressure overload. Basic Res Cardiol 108:324
Whelan, Russell S; Konstantinidis, Klitos; Xiao, Rui-Ping et al. (2013) Cardiomyocyte life-death decisions in response to chronic ?-adrenergic signaling. Circ Res 112:408-10

Showing the most recent 10 out of 43 publications