Abstract 1281: Activation of Apoptosis and Autophagy Post Myocardial Infarction With and Without Heart Failure
An important component of the remodeling that develops following myocardial infarction (MI) involves cell death, which can take the form of either necrosis or apoptosis. We examined the extent to which apoptosis and autophagy, a cellular degradation process responsible for the turnover of dysfunctional organelles and nonessential cytoplasmic proteins, participate in the remodeling process in monkeys (M. fascicularis). MI was induced in 6 monkeys by ligation of the left anterior descending coronary artery for 2 mos. There was no significant change in left ventricular (LV) dP/dt in MI vs sham monkeys (3840±279 vs 4,251±336 mmHg/sec), but LV end-diastolic pressure increased after MI (16±2 vs 5±1 mmHg). Compared to sham (n=4), the MI group was characterized by a significant (p<0.05) 2- to 3- fold upregulation of pro-apoptotic molecules (Bad, Bax, and cleaved caspase-3). TUNEL analysis demonstrated increased apoptosis (from 0.11±0.13 to 0.62±0.04 cells/mm2), but interestingly, the increase in apoptosis in non-myocytes was 10-fold higher than in myocytes in MI compared to sham. Proteins stimulating autophagy (cathepsin B, beclin1, Hsc73) did not show significant change in MI compared to sham, while an important negative mediator of autophagy, p-m TOR, was increased in MI (2-fold, p<0.05). Two months after MI, another 9 monkeys underwent a 3 week protocol of pacing induced (270b/min) heart failure (HF). LV dP/dt was reduced in HF (1,750±79 mmHg/sec; p<0.01), and LVEDP was increased (18±1 mmHg, p<0.01). The autophagic regulatory proteins cathepsin B, beclin1 and Hsc73 were increased significantly (2-to 4- fold, p<0.05) in HF group, and the negative mediator of autophagy, p-mTOR, was significantly decreased in HF (~46%, p<0.05) compared to MI, supporting the hypothesis that autophagy was induced during HF. These results suggest that apoptosis, but not autophagy, is involved in the cardiac remodeling process in MI. More severe stress, such as elicited by HF, is required to induce autophagy.