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mTOR-STAT3-notch signalling contributes to ALDH2-induced protection against cardiac contractile dysfunction and autophagy under alcoholism
- Source :
- Journal of Cellular and Molecular Medicine
- Publication Year :
- 2011
-
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.
- Subjects :
- STAT3 Transcription Factor
medicine.medical_specialty
autophagy
Notch
myocardial dysfunction
Reviews
Mice, Transgenic
030204 cardiovascular system & hematology
Biology
03 medical and health sciences
Mice
0302 clinical medicine
AMP-Activated Protein Kinase Kinases
Internal medicine
medicine
Animals
Myocytes, Cardiac
Phosphorylation
Receptor, Notch1
STAT3
Protein kinase B
PI3K/AKT/mTOR pathway
Cells, Cultured
030304 developmental biology
ALDH2
Cardioprotection
0303 health sciences
Ethanol
alcohol
Aldehyde Dehydrogenase, Mitochondrial
TOR Serine-Threonine Kinases
Autophagy
AMPK
Cell Biology
Aldehyde Dehydrogenase
Myocardial Contraction
3. Good health
Alcoholism
Endocrinology
Gene Expression Regulation
biology.protein
Molecular Medicine
Protein Kinases
Proto-Oncogene Proteins c-akt
Signal Transduction
Subjects
Details
- ISSN :
- 15824934
- Volume :
- 16
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal of cellular and molecular medicine
- Accession number :
- edsair.doi.dedup.....38c3ebe8664325e18cb794886ea04c82