title: Sestrin2 promotes LKB1-mediated AMPK activation in the ischemic heart.
abstract: The regulation of AMPK in the ischemic heart remains incompletely understood. Recent evidence implicates the role of Sestrin2 in the AMPK signaling pathway, and it is hypothesized that Sestrin2 plays an influential role during myocardial ischemia to promote AMPK activation. Sestrin2 protein was found to be expressed in adult cardiomyocytes and accumulated in the heart during ischemic conditions. Sestrin2 knockout (KO) mice were used to determine the importance of Sestrin2 during ischemia and reperfusion (I/R) injury. When wild-type (WT) and Sestrin2 KO mice were subjected to in vivo I/R, myocardial infarct size was significantly greater in Sestrin2 KO compared with WT hearts. Similarly, Langendorff perfused hearts indicated exacerbated postischemic contractile function in Sestrin2 KO hearts compared with WT. Ischemic AMPK activation was found to be impaired in the Sestrin2 KO hearts. Immunoprecipitation of Sestrin2 demonstrated an association with AMPK. Moreover, liver kinase B1 (LKB1), a major AMPK upstream kinase, was associated with the Sestrin2-AMPK complex in a time-dependent manner during ischemia, whereas this interaction was nearly abolished in Sestrin2 KO hearts. Thus, Sestrin2 plays an important role in cardioprotection against I/R injury, serving as an LKB1-AMPK scaffold to initiate AMPK activation during ischemic insults.
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York, USA;
authors.forename: Alex
authors.initials: A
authors.lastname: Morrison
authors.affiliation: Department of Pharmacology, College of Basic Medicine, Jilin University, Changchun, Jilin, China;
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York, USA;
authors.forename: Jinli
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, College of Basic Medicine, Jilin University, Changchun, Jilin, China;
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Capital Medical University, Beijing, China;
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York, USA;
authors.forename: Yina
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, USA;
authors.forename: Andrei
authors.initials: A
authors.lastname: Budanov
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA; and.
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York, USA; jli23@buffalo.edu.
authors.forename: Ji
authors.initials: J
authors.lastname: Li
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009203:Myocardial Infarction; D017202:Myocardial Ischemia / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology*; D010544:Peroxidases; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015427:Reperfusion Injury; D000084622:Sestrins
chemical_list: D055372:AMP-Activated Protein Kinases; D009687:Nuclear Proteins; D010544:Peroxidases; D017346:Protein Serine-Threonine Kinases; C529380:Sesn2 protein, mouse; D000084622:Sestrins; C491654:Stk11 protein, mouse
keywords: AMP-activated protein kinase; ischemia; scaffold protein