Abstract 79: Autophagy Is Necessary in Reversal of Left Ventricular Hypertrophy
Myocardial hypertrophy occurs in response to a variety of stresses as a compensatory mechanism to maintain cardiac output and normalize wall stress. Left ventricular hypertrophy (LVH) in the long term is an independent risk factor for a range of adverse consequences, such as cardiac dysfunction and cardiac mortality. Therefore, prevention or regression of LVH can be a major therapeutic target. Although reversal of LVH occurs after control of etiological factors, the molecular mechanisms remain to be clarified. We have previously reported that inhibition of autophagy, an evolutionarily conserved process for the bulk degradation of cytoplasmic components, induces cardiomyocyte hypertrophy.
In the present study, we investigated the role of autophagy in the course of reversal of LVH. Wild-type mice showed left ventricular hypertrophy by continuous injection of angiotensin II (A-II) for 14 days using osmotic mini-pump, and LVH was reversed 7 days after removal of pump. Autophagy was induced after removal of pump, as evidenced by an increase in LC3-II protein levels. Next, we crossed floxed Atg5 mice with transgenic mice expressing Cre recombinase in cardiac specific manner to generate cardiac-specific autophagy-deficient mice (CKO). We subjected CKO and control mice (CTL) to continuous injection of A-II for 14 days. CKO and CTL showed LVH similarly (LV weight/body weight, CKO 4.60±0.16 versus CTL 4.44±0.08, p=n.s., LV mass index, CKO 69.0±5.5 versus CTL 72.1±2.2, p=n.s.) without showing contractile dysfunction 14 days after injection of A-II. Cross-sectional area of cardiomyocytes was similar in CKO and CTL (CKO 281.0±1.0 μm2 versus CTL 274.0±1.5 μm2, p=n.s.). 7days after removal of pump, CKO showed significantly less reversal of LVH compared with CTL (LV weight/body weight, CKO 4.30±0.13 versus CTL 3.65±0.09, p<0.05, LV mass index, CKO 67.8±3.8 versus CTL 56.2±2.6, p<0.05). Cross-sectional area of cardiomyocytes also showed less reversal of LVH in CKO (CKO 270.6.0±7.0 μm2 versus CTL 220.9±11.4 μm2, p<0.05), indicating that reversal of LVH didn’t occur sufficiently in autophagy-deficient heart. Autophagy was suppressed during reversal of LVH in CKO. These results suggest that autophagy is necessary in reversal of LVH.
- © 2012 by American Heart Association, Inc.