Irisin alleviates pressure overload-induced cardiac hypertrophy by inducing protective autophagy via mTOR-independent activation of the AMPK-ULK1 pathway. (August 2018)

• Record Type: Journal Article
• Authors: Li, Ru-Li; Wu, Si-Si; Wu, Yao; Wang, Xiao-Xiao; Chen, Hong-Ying; Xin, Juan-juan; Li, He; Lan, Jie; Xue, Kun-Yue; Li, Xue; Zhuo, Cai-Li; Cai, Yu-Yan; He, Jin-Han; Zhang, Heng-Yu; Tang, Chao-Shu; Wang, Wang; Jiang, Wei
• Is Part Of: Journal of molecular and cellular cardiology. Volume 121(2018)
• Page Start: 242
• Page End: 255
• Publication Date: 2018-08
• Subjects: Irisin -- Cardiac hypertrophy -- Transverse aortic constriction -- Autophagy flux -- AMPK -- ULK1; 3-MA 3-methyladenine -- AMPK adenosine 5′-monophosphate (AMP)-activated protein kinase -- Ang-II angiotensin II -- ANP atrial natriuretic peptide -- ATG5 autophagy related 5 -- BNP brain natriuretic peptide -- CC compound C -- CK creatine kinase -- CK-MB creatine kinase-MB -- CO cardiac output -- CQ chloroquine -- DMSO dimethyl sulfoxide -- dPmax maximal value of the first derivative of LV pressure -- dPmin minimal value of the first derivative of LV pressure -- EDV end-diastolic volume -- EF ejection fraction -- ERK extracellular regulated protein kinase -- ESV end-systolic volume -- FNDC4 fibronectin type III domain-containing protein 4 -- FNDC5 fibronectin type III domain-containing protein 5 -- FS fractional shortening -- GFP green fluorescent protein -- JNK c-Jun N-terminal kinase -- KO knock-out -- LC3B-I nonlipidated form of LC3B -- LC3B-II lipidated form of LC3B -- LDH lactate dehydrogenase -- LV left ventricular -- LVEDD LV end diastolic diameter -- LVEDV LV end-diastolic volume -- LVEDP LV end-diastolic pressure -- LVESP LV end-systolic pressure -- LVIDs LV internal dimension in systole -- LVIDd LV internal dimension in diastole -- LVP LV pressure -- LVPWd LV posterior wall thickness at end-diastole -- LVSd left ventricle systolic diameter -- LVW/TL left heart ventricle weight/tibia length -- mTOR mammalian target of rapamycin -- NRCMs neonatal rat cardiomyocytes -- PE phenylephrine -- PGC-1α peroxisome proliferator-activated receptor-γ coactivator 1α -- RFP red fluorescent protein -- SQSTM1 sequestosome 1 -- SV stroke volume -- TAC transverse aortic constriction -- KO knockout -- Tg transgenice -- ULK1 Serine/threonine-protein kinase -- WT wild type; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2018.07.250
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: In hypertrophic hearts, autophagic flux insufficiency is recognized as a key pathology leading to maladaptive cardiac remodeling and heart failure. This study aimed to illuminate the cardioprotective role and mechanisms of a new myokine and adipokine, irisin, in cardiac hypertrophy and remodeling. Adult male wild-type, mouse- FNDC5 (irisin-precursor)-knockout and FNDC5 transgenic mice received 4 weeks of transverse aortic constriction (TAC) alone or combined with intraperitoneal injection of chloroquine diphosphate (CQ). Endogenous FNDC5 ablation aggravated and exogenous FNDC5 overexpression attenuated the TAC-induced hypertrophic damage in the heart, which was comparable to the protection of irisin against cardiomyocyte hypertrophy induced by angiotensin II (Ang II) or phenylephrine (PE). Accumulated autophagosome and impaired autophagy flux occurred in the TAC-treated myocardium and Ang II- or PE-insulted cardiomyocytes. Irisin deficiency caused reduced autophagy and aggravated autophagy flux failure, whereas irisin overexpression or supplementation induced protective autophagy and improved autophagy flux, which were reversed by autophagy inhibitors Atg5 siRNA, 3-MA and CQ. Irisin boosted the activity of only AMPK but not Akt and MAPK family members in hypertrophic hearts and cultured cardiomyocytes and further activated ULK1 at Ser555 but not Ser757 and did not affect the mTOR-S6K axis. Blockage of AMPK and ULK1 with compund C and SBI-0206965, respectively, both abrogated irisin's protection against cardiomyocyte hypertrophic injury and reversed its induction of both autophagy and autophagy flux. Our results suggest that irisin protects against pressure overload-induced cardiac hypertrophy by inducing protective autophagy and autophagy flux via activating AMPK-ULK1 signaling. Highlights: Irisin is highly expressed in mouse hearts. FNDC5 deletion aggravated and FNDC5 overexpression ameliorated the left ventricle hypertrophy, remodeling, injury and dysfunction induced by pressure overload. Irisin supplementation attenuated hypertrophy in Ang II– or phenylephrine-induced cardiomyocytes. Irisin alleviated cardiomyocyte hypertrophy in vivo and in vitro by inducing beneficial autophagy and autophagy influx via AMPK-ULK1 signaling but independent of mTOR.