Abstract：
AIMS:In myocardial ischemia-reperfusion (MI/R) injury, impaired autophagy function worsens cardiomyocyte death. AMP-activated protein kinase (AMPK) is a heterotrimeric protein that plays an important role in cardioprotection and myocardial autophagic function. AMPKα1 and α2 are localized primarily in the cytoplasm and nucleus, respectively, in cardiomyocytes, but the isoform-specific autophagy regulation of AMPK during MI/R remains unclear. MATERIALS AND METHODS:An MI/R model was built, and the protein expression of AMPKα1/α2, p-AMPK, mTOR, p-mTOR, TFEB, p-FoxO3a, SKP2, CARM1, TBP, Atg5, LAMP2, LC3B, and p62 during ischemia and reperfusion was determined by western blotting. Recombinant adeno-associated virus (serotype 9) vectors carrying tandem fluorescent-tagged LC3 or mRFP-GFP-LC3/GFP-LC3 were used to evaluate the autophagy status. AMPKα2 knockout mice were used for in vivo studies. KEY FINDINGS:Both cytoplasmic AMPKα1 and nuclear α2 subunit expression decreased during the reperfusion period, which led to AMPKα1-mTOR-TFEB and AMPKα2-Skp2-CARM1-TFEB signaling inhibition, respectively. The decreased TFEB level during reperfusion suppressed autophagy. Metformin could activate both the AMPKα1- and α2- mediated pathways, thus restoring autophagy flux during reperfusion. Nevertheless, in AMPKα2 knockout mice, nuclear α2-regulated Skp2-CARM1-TFEB signaling was inhibited, while α1-related signaling was comparatively unaffected, which partially impaired metformin-enhanced autophagy. SIGNIFICANCE:Our study suggests that metformin had the dual effects of promoting both cytoplasmic AMPKα1- and nuclear AMPKα2-related signaling to improve autophagic flux and restore cardiac function during MI/R.
journal_name
Life Scijournal_title
Life sciencesauthors
Wang Y,Yang Z,Zheng G,Yu L,Yin Y,Mu N,Ma Hdoi
10.1016/j.lfs.2019.04.002subject
Has Abstractpub_date
2019-05-15 00:00:00pages
64-71eissn
0024-3205issn
1879-0631pii
S0024-3205(19)30252-8journal_volume
225pub_type
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