Abstract 18552: Ulk1-Dependent Mitochondrial Autophagy Protects the Heart Against Pressure Overload-Induced Heart Failure
Mitochondrial autophagy (MA) degrades damaged mitochondria during heart failure. MA is activated after transverse aortic constriction (TAC) with a time course distinct from general autophagy, suggesting that MA is activated by a mechanism distinct from conventional autophagy. In order to elucidate the mechanism of MA during pressure overload (PO), loss-of-function mouse models of autophagy, including beclin1 systemic heterozygous knockout (KO) (beclin1-hetKO), atg7 cardiac-specific KO (atg7-CKO), and ulk1cardiac-specific KO (ulk1-CKO) mice, and respective control mice were subjected to TAC for 7-28 days. In electron microscopic analyses, MA was observed in control and atg7-CKO mice (0.32±0.04%, 0.93±0.57%; MA number/mitochondria number) but rarely in beclin 1-hetKO (0.02±0.02%) and ulk1-CKO mice (0.01±0.02%) at 7 days of TAC. Cox I/GAPDH and mitochondrial DNA content, indexes of mitochondrial content, were significantly decreased in control and atg7-CKO but were increased in beclin 1-hetKO mice and ulk1-CKO mouse hearts at 7 days of TAC. These results suggest that both Beclin1 and Ulk1 mediate MA in response to PO. As expected, LC3-II, an index of conventional autophagy, was significantly decreased and more p62 was accumulated in control, atg7-CKO, and beclin 1-hetKO mice but not in ulk1-CKO mice at 14 days of TAC, suggesting that PO-induced activation of conventional autophagy is Beclin 1- and Atg7-dependent. Left ventricular ejection fraction (EF) was decreased at 7 days (60.4±3.5, 75.6±1.7, p<0.05), and gradually decreased thereafter (47.0±5.4, 56.8±1.7 p<0.05) in beclin 1-hetKO compared to control mice. In atg7-CKO mice, although EF was decreased at 7 days (54.0±2.3%, p<0.05), it was maintained thereafter (57.2±5.7%, p<0.05). Interestingly, EF was maintained in the acute phase [dz1] (78.2±3.2%), whereas it was decreased thereafter (45.3±5.3%, p<0.05) in ulk1-CKO mice. In summary, both Beclin1 and Atg7 mediate conventional autophagy, whereas Beclin1 and Ulk1 mediate MA in response to PO. Beclin1/Atg7-dependent general autophagy protects the heart during the acute phase, whereas Beclin1/Ulk1-mediated MA protects the heart during the later phase of PO-induced cardiac hypertrophy.
Author Disclosures: A. Shirakabe: None. Y. Ikeda: None. T. Saito: None. P. Zai: None. J. Sadoshima: None.
- © 2016 by American Heart Association, Inc.