title: A novel cardioprotective p38-MAPK/mTOR pathway.
abstract: Despite intensive study, the mechanisms regulating activation of mTOR and the consequences of that activation in the ischemic heart remain unclear. This is particularly true for the setting of ischemia/reperfusion (I/R) injury. In a mouse model of I/R injury, we observed robust mTOR activation, and its inhibition by rapamycin increased injury. Consistent with the in-vivo findings, mTOR activation was also protective in isolated cardiomyocytes exposed to two models of I/R. Moreover, we identify a novel oxidant stress-activated pathway regulating mTOR that is critically dependent on p38-MAPK and Akt. This novel p38-regulated pathway signals downstream through REDD1, Tsc2, and 14-3-3 proteins to activate mTOR and is independent of AMPK. The protective role of p38/Akt and mTOR following oxidant stress is a general phenomenon since we observed it in a wide variety of cell types. Thus we have identified a novel protective pathway in the cardiomyocyte involving p38-mediated mTOR activation. Furthermore, the p38-dependent protective pathway might be able to be selectively modulated to enhance cardio-protection while not interfering with the inhibition of the better-known detrimental p38-dependent pathways.
authors: Department of Physiology, School of Medicine, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain. gonzalo.hernandez@usc.es
authors: Gonzalo
authors: G
authors: Hernández
authors: Hind
authors: H
authors: Lal
authors: Miguel
authors: M
authors: Fidalgo
authors: Ana
authors: A
authors: Guerrero
authors: Juan
authors: J
authors: Zalvide
authors: Thomas
authors: T
authors: Force
authors: Celia M
authors: CM
authors: Pombo
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; C469992:Ddit4 protein, mouse; D016877:Oxidants; D017382:Reactive Oxygen Species; C000624653:TSC2 protein, human; D014157:Transcription Factors; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases