title: mTOR-STAT3-notch signalling contributes to ALDH2-induced protection against cardiac contractile dysfunction and autophagy under alcoholism.
abstract: 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 β-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 γ-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.
authors: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Wei
authors: W
authors: Ge
authors: Jun
authors: J
authors: Ren
references: Nat Med. 2007 May;13(5):619-24
references: 17450150
references: Med Hypotheses. 2011 Mar;76(3):427-8
references: 21146322
references: Circ Res. 2008 Aug 15;103(4):343-51
references: 18703786
references: Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5012-7
references: 20194747
references: Circulation. 2010 Aug 24;122(8):771-81
references: 20697027
references: Science. 2008 Sep 12;321(5895):1493-5
references: 18787169
references: Biochim Biophys Acta. 2010 Dec;1806(2):220-9
references: 20637264
references: Alcohol. 2004 Apr;32(3):175-86
references: 15282111
references: Blood. 2007 Jul 1;110(1):278-86
references: 17363738
references: Oncogene. 2008 Dec;27 Suppl 1:S137-48
references: 19641499
references: Proc Am Thorac Soc. 2010 Feb;7(1):48-53
references: 20160148
references: Ann Intern Med. 1994 Apr 1;120(7):529-36
references: 8116990
references: Eur Heart J. 2011 Apr;32(8):1025-38
references: 20705694
references: Free Radic Biol Med. 2001 Dec 15;31(12):1539-43
references: 11744327
references: Alcohol Alcohol. 2006 Nov-Dec;41(6):585-92
references: 17020909
references: Antioxid Redox Signal. 2009 Aug;11(8):1975-88
references: 19327038
references: J Mol Cell Cardiol. 2006 Feb;40(2):283-94
references: 16403513
references: PLoS One. 2010 Jun 23;5(6):e11268
references: 20585647
references: Ther Adv Cardiovasc Dis. 2008 Dec;2(6):497-506
references: 19124444
references: Autophagy. 2010 Nov;6(8):1212-3
references: 20935489
references: Cell. 2002 Jul 26;110(2):163-75
references: 12150925
references: Pharmacol Ther. 2003 Mar;97(3):223-61
references: 12576135
references: World J Gastroenterol. 2009 Mar 14;15(10):1178-85
references: 19291817
references: J Biol Chem. 2004 Mar 19;279(12):11244-52
references: 14722101
references: J Am Coll Cardiol. 2009 Dec 1;54(23):2187-96
references: 19942091
references: J Clin Invest. 2010 Jan;120(1):103-14
references: 20038814
references: Arterioscler Thromb Vasc Biol. 2002 Mar 1;22(3):469-75
references: 11884292
references: Curr Opin Crit Care. 2001 Oct;7(5):337-43
references: 11805530
references: Circulation. 2009 Apr 14;119(14):1941-9
references: 19332462
references: Autophagy. 2007 Sep-Oct;3(5):496-8
references: 17617738
references: Circ Res. 2007 Mar 2;100(4):474-88
references: 17332438