Aldehyde dehydrogenase 2 ameliorates doxorubicin-induced myocardial dysfunction through detoxification of 4-HNE and suppression of autophagy.

Abstract

Mitochondrial aldehyde dehydrogenase (ALDH2) protects against cardiac injury via reducing production of 4-hydroxynonenal (4-HNE) and ROS. This study was designed to examine the impact of ALDH2 on doxorubicin (DOX)-induced cardiomyopathy and mechanisms involved with a focus on autophagy. 4-HNE and autophagic markers were detected by Western blotting in ventricular tissues from normal donors and patients with idiopathic dilated cardiomyopathy. Cardiac function, 4-HNE and levels of autophagic markers were detected in WT, ALDH2 knockout or ALDH2 transfected mice treated with or without DOX. Autophagy regulatory signaling including PI-3K, AMPK and Akt was examined in DOX-treated cardiomyocytes incubated with or without ALDH2 activator Alda-1. DOX-induced myocardial dysfunction, upregulation of 4-HNE and autophagic proteins were further aggravated in ALDH2 knockout mice while they were ameliorated in ALDH2 transfected mice. DOX downregulated Class I and upregulated Class III PI3-kinase, the effect of which was augmented by ALDH2 deletion. Accumulation of 4-HNE and autophagic protein markers in DOX-induced cardiomyocytes was significantly reduced by Alda-1. DOX depressed phosphorylated Akt but not AMPK, the effect was augmented by ALDH2 knockout. The autophagy inhibitor 3-MA attenuated, whereas autophagy inducer rapamycin mimicked DOX-induced cardiomyocyte contractile defects. In addition, rapamycin effectively mitigated Alda-1-offered protective action against DOX-induced cardiomyocyte dysfunction. Our data further revealed downregulated ALDH2 and upregulated autophagy levels in the hearts from patients with dilated cardiomyopathy. Taken together, our findings suggest that inhibition of 4-HNE and autophagy may be a plausible mechanism underscoring ALDH2-offered protection against DOX-induced cardiac defect. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy".

• Authors: Aijun Sun, Yong Cheng, Yingmei Zhang, Qian Zhang, Shijun Wang, Shan Tian, Yunzeng Zou, Kai Hu, Jun Ren, Junbo Ge
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 71 Pg. 92-104 (Jun 2014) ISSN: 1095-8584 [Electronic] England
• PMID: 24434637 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Aldehydes
• Doxorubicin
• ALDH2 protein, mouse
• Aldehyde Dehydrogenase
• Aldehyde Dehydrogenase, Mitochondrial
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• 4-hydroxy-2-nonenal

Topics

• Aldehyde Dehydrogenase (deficiency, genetics, metabolism)
• Aldehyde Dehydrogenase, Mitochondrial
• Aldehydes (metabolism)
• Animals
• Autophagy (drug effects)
• Cardiomyopathies (chemically induced, enzymology, metabolism)
• Down-Regulation (drug effects)
• Doxorubicin (pharmacology)
• Female
• Heart (drug effects, physiopathology)
• Humans
• Inactivation, Metabolic
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Myocardial Contraction (drug effects)
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (drug effects, metabolism, physiology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Random Allocation
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Up-Regulation (drug effects)