A dreadful consequence of myocardial infarction (MI) is cardiac remodeling, a process modifying ventricular shape and function as a consequence of increased load, decreased contractility and neurohormonal regulation. At the molecular level, ventricular remodeling is largely modulated by the activation of matrix metalloproteases. Our Preliminary Data demonstrate that this process of post-ischemic remodeling is also controlled by the activity of the proteasome, the main pathway of degradation of intracellular proteins. Specifically, we found that proteasome activity increases in a context of post-ischemic volume overload, and that blocking such activation with proteasome inhibitors reverses ventricular remodeling in terms of extracellular matrix accumulation, myocyte hypertrophy, and loss of contractile function. This is a novel and unexpected observation. Therefore, we propose to explore further the mechanisms by which the proteasome regulates cardiac remodeling and scar formation after MI. It is our global hypothesis that proteasome activation after coronary artery occlusion promotes scar formation at the early stage but, in the long term, increases collagen accumulation and cardiac hypertrophy, and thereby accelerates the transition into heart failure. We hypothesize that blocking this process will reverse post-ischemic remodeling when applied after the occurrence of irreversible ischemic damage. This hypothesis will be tested through three Specific Aims. 1. We will test the impact of proteasome inhibition, as compared to matrix metalloproteases inhibition, on the parameters of post-ischemic ventricular remodeling. 2. We will determine the impact of proteasome activity at the acute phase of myocardial infarction in terms of scar formation and of the risk of cardiac rupture. 3. We will determine whether the cardiac proteasome can be inhibited by a biological, as opposed to pharmacological, approach. Taken together, we expect that these Aims will answer the two following questions. 1. What are the mechanisms involved, in terms of extracellular matrix, myocyte size and function, and proteasome composition and structure that may explain the observed effects? 2. Based on these mechanisms, could we reproduce such effects in an alternative, biological and hypothesis-driven approach, for example with genetically-modified mouse models? On a clinical perspective, this proposal may open novel therapeutic avenues by deciphering molecular mechanisms that could not only prevent further progression of cardiac remodeling, but also, and more importantly, that could reverse this adverse process.
A dreadful consequence of myocardial infarction (MI) is cardiac remodeling, a process modifying ventricular shape and function as a consequence of increased load, decreased contractility and neurohormonal regulation. Our Preliminary Data demonstrate that this process of post-ischemic remodeling is controlled by the activity of the proteasome, the main pathway of degradation of intracellular proteins. Therefore, we propose to explore further the mechanisms by which the proteasome regulates cardiac remodeling and scar formation after MI. On a clinical perspective, this proposal may open novel therapeutic avenues by deciphering molecular mechanisms that could not only prevent further progression of cardiac remodeling, but also, and more importantly, that could reverse this adverse process.
| Shanmugam, Mayilvahanan; Molina, Cristina E; Gao, Shumin et al. (2011) Decreased sarcolipin protein expression and enhanced sarco(endo)plasmic reticulum Ca2+ uptake in human atrial fibrillation. Biochem Biophys Res Commun 410:97-101 |
