title: The AMPK Agonist PT1 and mTOR Inhibitor 3HOI-BA-01 Protect Cardiomyocytes After Ischemia Through Induction of Autophagy.
abstract: Myocardial ischemia has become one of the main causes of sudden cardiac death worldwide. Autophagy has been demonstrated to protect cardiomyocytes from ischemia/reperfusion (I/R)-induced damage. A novel small molecule compound 2-Chloro-5-[[5-[[5-(4,5-Dimethyl-2-nitrophenyl)-2-furanyl]methylene]-4,5-dihydro-4-oxo-2-thiazolyl]amino]benzoic acid (PT1) has been previously shown to specifically activate 5'-adenosine monophosphate-activated protein kinase (AMPK). Because AMPK activation effectively induces autophagy, we tested the protective efficacy of PT1 on cardiomyocytes after oxygen glucose deprivation/reoxygenation (OGD/R) in vitro. Mouse neonatal cardiomyocytes were treated with PT1 after OGD/R. 3-[4-(1,3-benzodioxol-5-yl)-2-oxo-3-buten-1-yl]-3-hydroxy-1,3-dihydro-2H-indol-2-one (3HOI-BA-01), a novel small compound showing potent inhibitory effect on mammalian target of rapamycin (mTOR) activation, was also tested for its cardioprotective effect, based on the established relationship between mTOR signaling and autophagy. Cell survival and autophagy-related signal pathways were examined after treatment with these agents. Our data indicate that both PT1 and 3HOI-BA-01 enhance cell survival after OGD/R. As expected, both PT1 and 3HOI-BA-01 induced autophagy in cardiomyocytes through activating AMPK pathway and inhibiting mTOR signaling, respectively. Induction of autophagy by PT1 and 3HOI-BA-01 was responsible for their cardioprotective effect, since inhibition of autophagy abolished the protective efficacy. Furthermore, simultaneous administration of PT1 and 3HOI-BA-01 profoundly upregulated autophagy after OGD/R and significantly promoted survival of cardiomyocytes. In vivo administration of PT1 and 3HOI-BA-01 in a murine myocardial (I/R injury model remarkably reduced infarct size and induced autophagy. Taken together, our research suggests that PT1 and 3HOI-BA-01 could be promising therapeutic agents for myocardial ischemia.
authors: Department of Cardiology, The Central Hospital of Wuhan, Wuhan, China huangling@whu.edu.cn.
authors: Ling
authors: L
authors: Huang
authors: Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China.
authors: Kai
authors: K
authors: Dai
authors: Department of Cardiology, The Central Hospital of Wuhan, Wuhan, China.
authors: Manhua
authors: M
authors: Chen
authors: Department of Cardiology, The Central Hospital of Wuhan, Wuhan, China.
authors: Wenping
authors: W
authors: Zhou
authors: Department of Cardiology, The Central Hospital of Wuhan, Wuhan, China.
authors: Xiaoling
authors: X
authors: Wang
authors: Department of Emergency, Renmin Hospital of Wuhan University, Wuhan, China.
authors: Jing
authors: J
authors: Chen
authors: Department of Cardiology, The Central Hospital of Wuhan, Wuhan, China.
authors: Wei
authors: W
authors: Zhou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D052117:Benzodioxoles / Q000494:pharmacology*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D019610:Cytoprotection; D004195:Disease Models, Animal; D005947:Glucose / Q000172:deficiency; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D062368:meta-Aminobenzoates / Q000494:pharmacology*
chemical_list: C000611054:2-chloro-5-((5-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-4-oxo-2-thiazolyl)amino)benzoic acid; C586450:3-(4-(benzo(d)(1,3)dioxol-5-yl)-2-oxobut-3-en-1-yl)-3-hydroxyindolin-2-one; D052117:Benzodioxoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D062368:meta-Aminobenzoates; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D010100:Oxygen
keywords: AMPK; autophagy; cardiomyocyte; ischemia; mTOR