PMID- 21609394 OWN - NLM STAT- MEDLINE DCOM- 20120615 LR - 20211203 IS - 1582-4934 (Electronic) IS - 1582-1838 (Print) IS - 1582-1838 (Linking) VI - 16 IP - 3 DP - 2012 Mar TI - mTOR-STAT3-notch signalling contributes to ALDH2-induced protection against cardiac contractile dysfunction and autophagy under alcoholism. PG - 616-26 LID - 10.1111/j.1582-4934.2011.01347.x [doi] AB - Mitochondrial aldehyde dehydrogenase-2 (ALDH2) has been shown to benefit myopathic changes following alcohol intake, although the precise mechanism is still unclear. This study was designed to evaluate the role of ALDH2 on chronic alcohol intake-induced myocardial geometric and functional damage with a focus on autophagic signalling. Wild-type friendly virus B (FVB) and transgenic mice overexpressing ALDH2 driven by chicken beta-actin promoter were fed a 4% alcohol liquid diet for 12 weeks. Cardiac geometry and function were assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate the essential autophagy markers, Akt and AMP-dependent protein kinase (AMPK) as well as their downstream signalling mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3). Alcohol intake altered cardiac geometry and function as demonstrated by lessened LV wall and septal thickness, enlarged end systolic and diastolic diameters, decreased fractional shortening and cell shortening, the effects of which were mitigated by ALDH2 transgene. Chronic alcohol intake triggered myocardial autophagy as shown by LC3B II isoform switch, as well as decreased phosphorylation of mTOR, the effects of which were ablated by ALDH2. Chronic alcohol intake suppressed phosphorylation of Akt and AMPK, which was reconciled by ALDH2. Levels of Notch1 and STAT3 phosphorylation were dampened by chronic alcohol intake in FVB but not ALDH2 myocardium. Moreover, the gamma-secretase Notch inhibitor N\xE2\x80\x90[N-(3,5-difluorophenacetyl)-1-alany1]-S-phenyglycine t-butyl ester exacerbated ethanol-induced cardiomyocyte contractile dysfunction, apoptosis and autophagy. In summary, these findings suggested that ALDH2 elicits cardioprotection against chronic alcohol intake-induced cardiac geometric and functional anomalies by inhibition of autophagy possibly via restoring the Akt-mTOR-STAT3-Notch signalling cascade. CI - (c) 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. FAU - Ge, Wei AU - Ge W AD - Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, China. FAU - Ren, Jun AU - Ren J LA - eng GR - R01 AA013412-02/AA/NIAAA NIH HHS/United States GR - R01 AA013412/AA/NIAAA NIH HHS/United States GR - R01 AA013412-03/AA/NIAAA NIH HHS/United States GR - R01 AA013412-04/AA/NIAAA NIH HHS/United States GR - 1R01 AA013412/AA/NIAAA NIH HHS/United States GR - R01 AA013412-05/AA/NIAAA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - England TA - J Cell Mol Med JT - Journal of cellular and molecular medicine JID - 101083777 RN - 0 (Notch1 protein, mouse) RN - 0 (Receptor, Notch1) RN - 0 (STAT3 Transcription Factor) RN - 0 (Stat3 protein, mouse) RN - 3K9958V90M (Ethanol) RN - EC 1.2.1.3 (ALDH2 protein, mouse) RN - EC 1.2.1.3 (Aldehyde Dehydrogenase) RN - EC 1.2.1.3 (Aldehyde Dehydrogenase, Mitochondrial) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases) SB - IM MH - AMP-Activated Protein Kinase Kinases MH - Alcoholism/*metabolism/pathology/physiopathology MH - Aldehyde Dehydrogenase/genetics/*metabolism MH - Aldehyde Dehydrogenase, Mitochondrial MH - Animals MH - Autophagy/*drug effects MH - Cells, Cultured MH - Ethanol/pharmacology MH - Gene Expression Regulation MH - Mice MH - Mice, Transgenic MH - Myocardial Contraction/*drug effects MH - Myocytes, Cardiac/drug effects/pathology/physiology MH - Phosphorylation MH - Protein Kinases/genetics/metabolism MH - Proto-Oncogene Proteins c-akt/genetics/metabolism MH - Receptor, Notch1/genetics/metabolism MH - STAT3 Transcription Factor/genetics/metabolism MH - Signal Transduction MH - TOR Serine-Threonine Kinases/genetics/metabolism PMC - PMC3202644 MID - NIHMS299220 EDAT- 2011/05/26 06:00 MHDA- 2012/06/16 06:00 PMCR- 2012/03/01 CRDT- 2011/05/26 06:00 PHST- 2011/05/26 06:00 [entrez] PHST- 2011/05/26 06:00 [pubmed] PHST- 2012/06/16 06:00 [medline] PHST- 2012/03/01 00:00 [pmc-release] AID - 10.1111/j.1582-4934.2011.01347.x [doi] PST - ppublish SO - J Cell Mol Med. 2012 Mar;16(3):616-26. doi: 10.1111/j.1582-4934.2011.01347.x.