title: AMPK inhibits cardiac hypertrophy by promoting autophagy via mTORC1.
abstract: AMPK, a serine/threonine protein kinase, has proven to be an important positive regulator of autophagy, which is a key factor in the regulation of cardiac hypertrophy. Thus, we explored whether AMPK could inhibit cardiac hypertrophy by regulating autophagy. In pressure overload induced cardiac hypertrophy, decreased autophagy was detected. Administration of AMPK activators (AICAR and metformin) significantly blocked hypertrophy, accompanied by enhanced autophagy level in the hearts. Furthermore, AMPK activation resulted in enhanced autophagosome formation and unimpaired lysosomal function. In vitro studies demonstrated adenoviral overexpression of constitutively activated AMPK increased autophagy and blunted PE-induced cardiomyocyte hypertrophy. Additionally, we found AICAR reduced the phosphorylation of the mTORC1 downstream effectors 4EBP1 and p70S6K, but AKT, which is a downstream signal of mTORC2, was not affected. Furthermore, activation by AMPK failed to lead to an additive effect on autophagy induced by the mTORC1 inhibitor rapamycin, indicating AMPK activates autophagy through the inhibition of mTORC1 but not of mTORC2. This study proved that AMPK can inhibit cardiac hypertrophy by stimulating autophagy through mTORC1 signaling.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
authors.forename: Yanh
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
authors.forename: Fengj
authors.initials: F
authors.lastname: Yao
authors.affiliation: Animal Research Center of the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Su
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
authors.forename: Ruic
authors.initials: R
authors.lastname: Xue
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Dai
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Fang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
authors.forename: Juny
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
authors.forename: Yil
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
authors.forename: Huil
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
authors.forename: Yued
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Animal Research Center of the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Wenw
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China.
authors.forename: Lil
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China. Electronic address: liuch75@mail.sysu.edu.cn.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510080, China. Electronic address: dongxg@mail.sysu.edu.cn.
authors.forename: Yug
authors.initials: Y
authors.lastname: Dong
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D006332:Cardiomegaly / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005786:Gene Expression Regulation; D006321:Heart / Q000503:physiopathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D011312:Pressure / Q000009:adverse effects; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Autophagy; Cardiac hypertrophy; mTORC1