Abstract 3554: Autophagy is Detrimental during Acute Phase but Protective during Chronic Phase after Myocardial Infarction
Autophagy is a bulk degradation process of proteins and organelles. Although autophagy is protective against certain stress, excessive induction of autophagy during pathological insults may lead to cell death. We investigated the functional significance of autophagy after myocardial infarction (MI). Left anterior descending coronary artery was permanently ligated in mice. Autophagosome (AP) formation in the border zone and MI area, as evaluated by GFP-LC3 dots in GFP-LC3 mice at Day 2 and LC3-II/LC3-I at Days 2–5, was significantly increased in MI mice compared with sham (p<0.01, n=5). Increases in AP after MI were significantly attenuated in beclin1+/− - GFP-LC3 bigenic mice (162.8±3.5 vs 23.7±2.2 dots, p<0.01). Kaplan-Meier analysis showed that rate of mortality at Days 0 –10 was significantly lower in beclin1+/− than in WT mice (p< 0.05), but was not different at Day 11–28. The size of MI determined by TTC staining at Day 3 was smaller in beclin1+/− than in WT mice (8.5±1.9 vs 26.3±0.8%, p<0.01, n=6), but Masson Trichrome staining at Day 28 showed larger infarction in beclin1+/− than in WT mice (37.6±1.8 vs 26.4±1.7%, p<0.01, n=10). LV ejection fraction was significantly greater in beclin1+/− than in WT mice at Day 4 (48.8±4.9 vs 33.8±3.1%, p<0.05, n=4), but it was not different at Day 28. Myocyte cross sectional area was not significantly different between beclin1+/− and WT mice at Day 4, however it was significantly greater in beclin1+/− than in WT mice (μm2, remote 221±2 vs 256±1, p<0.01, n=3; adjacent 320±4 vs. 351±2, p<0.01, n=10) at Day 28. Cardiac myocyte apoptosis was significantly greater in beclin1+/− than in WT mice (remote 0.14±0.03 vs 0.03±0.01%, p<0.01, n=11; adjacent 0.24±0.04 vs 0.13±0.02%, p<0.05, n=11) at Day 28. In contrast, the size of MI at day 4 determined by TTC was significantly larger in beclin1 overexpression transgenic (Tg-bec) than in WT mice (38.3±2.0 vs 24.2±1.8 %, p<0.01, n=4). Kaplan Meier analysis showed that the mortality was significantly greater in Tg-bec (6 out of 7) than in WT (3 out of 8) mice (p< 0.05) at Day 0 –7. These results suggest that, after MI, autophagy during the acute phase is detrimental whereas it may be protective during the chronic phase and prevent expansion of MI and LV dysfunction.