Richard N. Kitsis, M.D.
Professor, Department of Medicine (Cardiology)
Professor, Department of Cell Biology
Director, Wilf Family Cardiovascular Research Institute
The Dr. Gerald and Myra Dorros Chair in Cardiovascular Disease
Areas of Investigation
Dr. Richard Kitsis’ laboratory studies fundamental mechanisms of cell death and their role in cardiovascular disease. To accomplish this, a variety of approaches are employed including molecular and cellular biology, biochemistry, mouse and human genetics, and physiology.
- Demonstration that cardiac myocyte apoptosis plays causal roles in the pathogenesis of both myocardial infarction and heart failure – providing the initial “proof of concept” that apoptosis may be a novel therapeutic target in these important disorders (Foo et al. J Clin Invest, 2005. 115: 565-571).
- Demonstration of molecular mechanisms by which ARC, an endogenous inhibitor of apoptosis enriched in cardiac myocytes, simultaneously antagonizes both death receptor and mitochondrial central apoptosis pathways (Nam et al. Molecular Cell, 2004. 15: 901-912; Foo et al, 2007. Proc Natl Acad Sci USA, 2007. 104: 20826-20831). The ability of ARC to suppress both of these pathways is unique among apoptosis inhibitors.
- Demonstration of a new class of protein-protein interactions that mediates some actions of ARC.
- Demonstration that, in response to death stimuli, ARC undergoes degradation via the ubiquitin-proteasomal pathway, and that maintenance of ARC levels at only ~70% of baseline is adequate to inhibit cell death (Nam et al. J Biol Chem, 2007. 282: 5522-5528).
These results provide the basis for studies that address the following:
- The role of ARC in mediating infarct generation following ischemia-reperfusion and cardiac remodeling in heart failure in vivo. These studies employ a variety of already generated ARC knockout and inducible transgenic mice and are being carried out in collaboration with Dr. David Lefer, another trainer in this program.
- The importance of ARC’s interactions with Bax, Fas, and p53 in inhibiting apoptosis in vivo in various clinically-relevant models. These experiments involve matings between ARC-manipulated mice and mice deficient in each of these interacting proteins.
- Identification of the E3-ubiquitin ligase responsible for ARC degradation. This may provide a target for the development of drugs that inhibit ARC degradation during apoptosis and, thereby, maintain ARC levels during a critical period (e.g. during the early hours of myocardial infarction).
- Genetic variation in the human ARC gene with the goal of identifying variants that predispose to or protect from myocardial infarction.
- Molecular mechanisms of necrosis. A variety of approaches are being used to begin to delineate a blue print for this important form of cell death.
These basic and translational studies may provide the basis for new therapeutic approaches to myocardial infarction and heart failure.