Grant: Operating Grant - PA: Regional Partnership Program : Manitoba

Occurrence of heart failure in the survivors of heart attack (Myocardial Infarction, MI) is a common clinical syndrome with a grave prognosis. Because of the loss of the contractile elements due to MI, the heart responds by an increase in its muscle mass as well as by an activation of other neurohumoral compensatory processes to maintain perfusion pressure. In rats subjected to coronary ligation (myocardial infarction), we and others have shown that the activity of the protein called Tumor Necrosis Factor-alpha (TNF-alpha) increases and plays a causative role in the pathogenesis of heart failure. Yet, clinical trials employing anti TNF-alpha therapy were a failure indicating that our understanding of the molecular mechanisms is not complete. Thus the undertaking of clinical trials turned out to be a "premature" step. In the same experimental model, we have now shown that another protein, Interleukin-10 (IL-10), known for its cell survival effects decreases during heart failure. Therefore, we suggested that it may in fact be the ratio of IL-10/TNF-alpha, rather than TNF-alpha alone, which may have a critical role in heart failure. Furthermore, in isolated cardiomyocytes, we showed that IL-10 antagonized almost all of the deleterious effect of TNF-alpha in a very intricate manner. The present study, therefore, is designed to understand the molecular basis of the beneficial effects of IL-10, its innate signaling processes and to identify the molecular targets to promote its cardiomyocyte cell survival effects.