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Effects of Proteasome Inhibition on Cardiac Hypertrophy

by
Nadia Hedhli
Cell Biology and Molecular Medicine

B.A. Rutgers University

Thesis Advisor: Christophe Depre, M.D., Ph.D
Associate Professor
Department of Cell Biology and Molecular Medicine


Cell Biology and Molecular Medicine
MSB G-level
Conference Room

Wednesday, April 16, 2008
2:00 p.m.


Abstract

Our overall goal is to better understand the importance of proteasome regulation in a context of cardiac hypertrophy. To reach that objective, we analyzed successively a model of adaptive hypertrophy by over-expression of the chaperone H11K, a model of pressure overload, and a model of post-ischemic volume overload with extensive remodeling.
We demonstrate a regulation of the proteasome during cardiac hypertrophy mediated by H11K, which involves a change in expression, activity, composition and subcellular distribution. This study shows that proteasome inhibition can reduce H11K-induced pre- existing hypertrophy. Importantly, the data collected in vitro also show that the inhibition of the proteasome directly prevents cardiac cell growth induced by H11K over-expression or by well known pro-hypertrophic hormones, which at least partially results from the prevention of a stimulation of protein synthesis in such conditions.
Our second study shows that proteasome inhibition both prevents and reverses pressure induced cardiac hypertrophy. In particular, this investigation shows that proteasome inhibition can reverse ventricular remodeling. We show that proteasome inhibition after the onset of pressure overload improves cardiac function, reduces cardiac cell size and limits ventricular remodeling. These effects of proteasome inhibitors seem largely related to an inhibition of the NF-B-mediated accumulation of interstitial collagen through MMP activation.
Our third study shows that proteasome inhibition limits the extent of cardiac hypertrophy and remodeling upon volume overload following permanent coronary artery occlusion by decreasing myocyte hypertrophy, ventricular remodeling, and collagen accumulation while improving cardiac function. However, it increases the mortality in the acute phase, likely by blocking collagen synthesis.
The last part of our work shows that proteasome inhibition may potentially affect translation initiation by interfering with polysome assembly, in both models of H11K over-expression and pressure overload, and eEF1A expression.


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