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A novel protective mechanism for mitochondrial aldehyde dehydrogenase (ALDH2) in type i diabetes-induced cardiac dysfunction: role of AMPK-regulated autophagy.
- Source :
-
Biochimica et biophysica acta [Biochim Biophys Acta] 2015 Feb; Vol. 1852 (2), pp. 319-31. Date of Electronic Publication: 2014 May 27. - Publication Year :
- 2015
-
Abstract
- Mitochondrial aldehyde dehydrogenase (ALDH2) is known to offer myocardial protection against stress conditions including ischemia-reperfusion injury, alcoholism and diabetes mellitus although the precise mechanism is unclear. This study was designed to evaluate the effect of ALDH2 on diabetes-induced myocardial injury with a focus on autophagy. Wild-type FVB and ALDH2 transgenic mice were challenged with streptozotozin (STZ, 200mg/kg, i.p.) for 3months to induce experimental diabetic cardiomyopathy. Diabetes triggered cardiac remodeling and contractile dysfunction as evidenced by cardiac hypertrophy, decreased cell shortening and prolonged relengthening duration, the effects of which were mitigated by ALDH2. Lectin staining displayed that diabetes promoted cardiac hypertrophy, the effect of which was alleviated by ALDH2. Western blot analysis revealed dampened autophagy protein markers including LC3B ratio and Atg7 along with upregulated p62 following experimental diabetes, the effect of which was reconciled by ALDH2. Phosphorylation level of AMPK was decreased and its downstream signaling molecule FOXO3a was upregulated in both diabetic cardiac tissue and in H9C2 cells with high glucose exposure. All these effect were partly abolished by ALDH2 overexpression and ALDH2 agonist Alda1. High glucose challenge dampened autophagy in H9C2 cells as evidenced by enhanced p62 levels and decreased levels of Atg7 and LC3B, the effect of which was alleviated by the ALDH2 activator Alda-1. High glucose-induced cell death and apoptosis were reversed by Alda-1. The autophagy inhibitor 3-MA and the AMPK inhibitor compound C mitigated Alda-1-offered beneficial effect whereas the autophagy inducer rapamycin mimicked or exacerbated high glucose-induced cell injury. Moreover, compound C nullified Alda-1-induced protection against STZ-induced changes in autophagy and function. Our results suggested that ALDH2 protects against diabetes-induced myocardial dysfunction possibly through an AMPK -dependent regulation of autophagy. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.<br /> (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Subjects :
- Adenine analogs & derivatives
Adenine pharmacology
Aldehyde Dehydrogenase, Mitochondrial
Animals
Apoptosis drug effects
Autophagy-Related Protein-1 Homolog
Benzamides pharmacology
Benzodioxoles pharmacology
Calcium Signaling drug effects
Cardiotonic Agents metabolism
Cell Survival drug effects
Chickens
Diabetes Mellitus, Type 1 pathology
Forkhead Box Protein O3
Forkhead Transcription Factors metabolism
Glucose pharmacology
Heart drug effects
Membrane Potential, Mitochondrial drug effects
Mice, Transgenic
Mitochondria drug effects
Models, Biological
Myocardial Contraction drug effects
Myocytes, Cardiac drug effects
Myocytes, Cardiac metabolism
Myocytes, Cardiac pathology
Phosphorylation drug effects
Protein Serine-Threonine Kinases metabolism
Rats
Streptozocin
AMP-Activated Protein Kinases metabolism
Aldehyde Dehydrogenase metabolism
Autophagy drug effects
Diabetes Mellitus, Type 1 enzymology
Diabetes Mellitus, Type 1 physiopathology
Heart physiopathology
Mitochondria enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 0006-3002
- Volume :
- 1852
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta
- Publication Type :
- Academic Journal
- Accession number :
- 24874076
- Full Text :
- https://doi.org/10.1016/j.bbadis.2014.05.017