title: Mechanistic target of rapamycin complex 2 protects the heart from ischemic damage.
abstract: BACKGROUND
  The mechanistic target of rapamycin (mTOR) comprises 2 structurally distinct multiprotein complexes, mTOR complexes 1 and 2 (mTORC1 and mTORC2). Deregulation of mTOR signaling occurs during and contributes to the severity of myocardial damage from ischemic heart disease. However, the relative roles of mTORC1 versus mTORC2 in the pathogenesis of ischemic damage are unknown.
  
  
  RESULTS
  Combined pharmacological and molecular approaches were used to alter the balance of mTORC1 and mTORC2 signaling in cultured cardiac myocytes and in mouse hearts subjected to conditions that mimic ischemic heart disease. The importance of mTOR signaling in cardiac protection was demonstrated by pharmacological inhibition of both mTORC1 and mTORC2 with Torin1, which led to increased cardiomyocyte apoptosis and tissue damage after myocardial infarction. Predominant mTORC1 signaling mediated by suppression of mTORC2 with Rictor similarly increased cardiomyocyte apoptosis and tissue damage after myocardial infarction. In comparison, preferentially shifting toward mTORC2 signaling by inhibition of mTORC1 with PRAS40 led to decreased cardiomyocyte apoptosis and tissue damage after myocardial infarction.
  
  
  CONCLUSIONS
  These results suggest that selectively increasing mTORC2 while concurrently inhibiting mTORC1 signaling is a novel therapeutic approach for the treatment of ischemic heart disease.
authors.affiliation: From SDSU Heart Institute, Department of Biology, San Diego State University, San Diego, CA.
authors.forename: Mirko
authors.initials: M
authors.lastname: Völkers
authors.forename: Mathias H
authors.initials: MH
authors.lastname: Konstandin
authors.forename: Shirin
authors.initials: S
authors.lastname: Doroudgar
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Toko
authors.forename: Pearl
authors.initials: P
authors.lastname: Quijada
authors.forename: Shabana
authors.initials: S
authors.lastname: Din
authors.forename: Anya
authors.initials: A
authors.lastname: Joyo
authors.forename: Luis
authors.initials: L
authors.lastname: Ornelas
authors.forename: Kaitleen
authors.initials: K
authors.lastname: Samse
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Thuerauf
authors.forename: Natalie
authors.initials: N
authors.lastname: Gude
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Glembotski
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D009287:Naphthyridines / Q000494:pharmacology; D061251:Primary Cell Culture; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; C484523:AKT1S1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D046912:Multiprotein Complexes; D009287:Naphthyridines; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D011994:Recombinant Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: AKT1S1 protein, human; RICTOR protein, human; TOR serine-threonine kinases