PMID- 24008870
OWN - NLM
STAT- MEDLINE
DCOM- 20140128
LR  - 20211203
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Print)
IS  - 0009-7322 (Linking)
VI  - 128
IP  - 19
DP  - 2013 Nov 5
TI  - Mechanistic target of rapamycin complex 2 protects the heart from ischemic 
      damage.
PG  - 2132-44
LID - 10.1161/CIRCULATIONAHA.113.003638 [doi]
AB  - 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. METHODS 
      AND 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.
FAU - Volkers, Mirko
AU  - Volkers M
AD  - From SDSU Heart Institute, Department of Biology, San Diego State University, San 
      Diego, CA.
FAU - Konstandin, Mathias H
AU  - Konstandin MH
FAU - Doroudgar, Shirin
AU  - Doroudgar S
FAU - Toko, Haruhiro
AU  - Toko H
FAU - Quijada, Pearl
AU  - Quijada P
FAU - Din, Shabana
AU  - Din S
FAU - Joyo, Anya
AU  - Joyo A
FAU - Ornelas, Luis
AU  - Ornelas L
FAU - Samse, Kaitleen
AU  - Samse K
FAU - Thuerauf, Donna J
AU  - Thuerauf DJ
FAU - Gude, Natalie
AU  - Gude N
FAU - Glembotski, Christopher C
AU  - Glembotski CC
FAU - Sussman, Mark A
AU  - Sussman MA
LA  - eng
GR  - 2P01HL085577/HL/NHLBI NIH HHS/United States
GR  - R01 HL113656-02/HL/NHLBI NIH HHS/United States
GR  - R01 HL067245-12/HL/NHLBI NIH HHS/United States
GR  - R37 HL091102-06/HL/NHLBI NIH HHS/United States
GR  - R01 HL113647/HL/NHLBI NIH HHS/United States
GR  - R01 HL117163/HL/NHLBI NIH HHS/United States
GR  - R01 HL105759-03/HL/NHLBI NIH HHS/United States
GR  - R01 HL105759/HL/NHLBI NIH HHS/United States
GR  - R01 HL075573/HL/NHLBI NIH HHS/United States
GR  - R01 HL75573/HL/NHLBI NIH HHS/United States
GR  - R03 EB011698/EB/NIBIB NIH HHS/United States
GR  - R37 HL091102/HL/NHLBI NIH HHS/United States
GR  - R01 HL104535/HL/NHLBI NIH HHS/United States
GR  - P01 HL085577/HL/NHLBI NIH HHS/United States
GR  - R01 HL113647-01/HL/NHLBI NIH HHS/United States
GR  - R01 HL067245/HL/NHLBI NIH HHS/United States
GR  - R01 HL113656/HL/NHLBI NIH HHS/United States
GR  - R01 HL117163-01/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130905
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 
      (1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one)
RN  - 0 (AKT1S1 protein, human)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Carrier Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Naphthyridines)
RN  - 0 (RICTOR protein, human)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - 0 (Recombinant Proteins)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/metabolism
MH  - Animals
MH  - Apoptosis/physiology
MH  - Carrier Proteins/metabolism
MH  - Humans
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Multiprotein Complexes/*antagonists & inhibitors/genetics/*metabolism
MH  - Myocardial Infarction/*metabolism/pathology
MH  - Myocardial Ischemia/*metabolism/pathology
MH  - Myocytes, Cardiac/cytology/physiology
MH  - Naphthyridines/pharmacology
MH  - Primary Cell Culture
MH  - Rapamycin-Insensitive Companion of mTOR Protein
MH  - Recombinant Proteins/genetics/metabolism
MH  - Signal Transduction/drug effects/*physiology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/genetics/*metabolism
PMC - PMC4131547
MID - NIHMS600045
OTO - NOTNLM
OT  - AKT1S1 protein, human
OT  - RICTOR protein, human
OT  - TOR serine-threonine kinases
EDAT- 2013/09/07 06:00
MHDA- 2014/01/29 06:00
PMCR- 2014/08/13
CRDT- 2013/09/07 06:00
PHST- 2013/09/07 06:00 [entrez]
PHST- 2013/09/07 06:00 [pubmed]
PHST- 2014/01/29 06:00 [medline]
PHST- 2014/08/13 00:00 [pmc-release]
AID - CIRCULATIONAHA.113.003638 [pii]
AID - 10.1161/CIRCULATIONAHA.113.003638 [doi]
PST - ppublish
SO  - Circulation. 2013 Nov 5;128(19):2132-44. doi: 10.1161/CIRCULATIONAHA.113.003638. 
      Epub 2013 Sep 5.