Melatonin ameliorates pressure overload-induced cardiac hypertrophy by attenuating Atg5-dependent autophagy and activating the Akt/mTOR pathway

Chen-Nian Xu, Ling-Heng Kong, Peng Ding, Yang Liu, Zhen-Ge Fan, Er-He Gao, Jian Yang, Li-Fang Yang
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease2020
Cardiac hypertrophy, including hypertension and valvular dysfunction, is a pathological feature of many cardiac diseases that ultimately leads to heart failure. Melatonin confers a protective role against pathological cardiac hypertrophy, but the underlying mechanisms remain elusive. In the present study, we hypothesized that melatonin protects against pressure overload-induced cardiac hypertrophy by attenuating Atg5-dependent autophagy and activating the Akt/mTOR pathway. Male C57BL/6 mice that received adenovirus carrying cardiac-specific Atg5 (under the cTNT promoter; Ad-cTNT-Atg5) underwent transverse aortic constriction (TAC) or sham operation and received an intraperitoneal injection of melatonin (10 mg/kg/d), vehicle or LY294002 (10 mg/kg/d) for 8 weeks. Melatonin treatment for 8 weeks markedly attenuated cardiac hypertrophy and restored impaired cardiac function, as indicated by a decreased HW/BW ratio, reduced cell cross-sectional area and fibrosis, downregulated the mRNA levels of ANP, BNP, and β-MHC and ameliorated adverse effects on the LVEF and LVFS. Melatonin treatment also inhibited apoptosis and alleviated autophagy dysfunction. Furthermore, melatonin inhibited Akt/mTOR pathway activation, while these effects were blocked by LY294002. In addition, the effect of melatonin regulation on TAC-induced autophagy dysfunction was inhibited by LY294002 or cardiac-specific Atg5 overexpression. As expected, Akt/mTOR pathway inhibition or cardiac-specific Atg5 overexpression restrained melatonin alleviation of pressure overload-induced cardiac hypertrophy. These results demonstrated that melatonin ameliorated pressure overload-induced cardiac hypertrophy by attenuating Atg5-dependent autophagy and activating the Akt/mTOR pathway.
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