mTOR-STAT3-notch signalling contributes to ALDH2-induced protection against cardiac contractile dysfunction and autophagy under alcoholism.
mTOR-STAT3-notch signalling contributes to ALDH2-induced protection against cardiac contractile dysfunction and autophagy under alcoholism.
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DOI：
10.1111/j.1582-4934.2011.01347.x
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发表时间：
2012-03
影响因子：
5.3
通讯作者：
Ren J
中科院分区：
文献类型：
--
作者：
Ge W;Ren J
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-[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.
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影响因子：
2.3
作者：
Ren, Jun;Wold, Loren E
通讯作者：
Wold, Loren E
影响因子：
37.8
作者：
Koda K;Salazar-Rodriguez M;Corti F;Chan NY;Estephan R;Silver RB;Mochly-Rosen D;Levi R
通讯作者：
Levi R
影响因子：
13.3
作者：
Yokoyama, Tomohisa;Kondo, Yasuko;Kondo, Seiji
通讯作者：
Kondo, Seiji
影响因子：
24
作者：
Ma, Heng;Li, Ji;Ren, Jun
通讯作者：
Ren, Jun
影响因子：
5
作者：
Li, SY;Li, Q;Ren, J
通讯作者：
Ren, J