Abstract 1257: Autophagy Plays Both Protective and Detrimental Roles in Post Myocardial Infarction Hearts

Abstract

Autophagy is an important mechanism of protein degradation involving formation of double membrane vesicles termed autophagosomes and lysosomal degradation. Autophagy is activated in the heart both under basal conditions and in response to stress. During acute ischemia, autophagy is protective, but during reperfusion, it may promote cell death, suggesting that the function of autophagy is context-dependent. In order to elucidate the role of autophagy in other pathological conditions in the heart, we examined whether autophagy is activated after myocardial infarction (MI) in vivo. On Day 2, autophagosome formation, as evaluated by GFP-LC3 dots, was significantly increased in the border zone compared with the remote area (25 vs 2 dots/field, p<0.05, n=5). The functional significance of autophagy was evaluated using beclin 1 +/− mice, in which autophagy is significantly attenuated due to reduced expression of Beclin 1, a critical component of the autophagic machinery. Control (WT) and beclin 1 +/− mice (3 months old) were subjected to permanent coronary artery ligation. Kaplan Meier survival analyses indicated that the rate of mortality was significantly greater in WT (4 out of 13) than in beclin 1 +/− (0 out of 11) mice (p<0.05) at early stages (0 –11 days), whereas there was no significant difference in mortality at later stages (11–29 days), suggesting that inhibition of autophagy is protective during early stages of MI. After 4 weeks, beclin 1 +/− mice exhibited larger LV myocyte cross sectional areas in remote areas (254 vs 220 μm 2 , p<0.005) with greater posterior wall thickness (1.24 vs 1.11 mm, p<0.05) and increased levels of cardiac myocyte apoptosis in the scar area (7.6 vs 2.8/mm 2 ) and the adjacent area (1.2 vs 0.6/mm 2 ) compared with WT mice. These results suggest that suppression of autophagy at late stages of MI promotes apoptosis and hypertrophy, and may be detrimental. In summary, autophagy is induced in the heart after MI and exhibits time-dependent functions. Although autophagy is detrimental at early (within 11 days) stages of MI, it may inhibit cardiac remodeling, and, thus, is protective during chronic stages.