ALDH2 protects against alcoholic cardiomyopathy through a mechanism involving the p38 MAPK/CREB pathway and local renin-angiotensin system inhibition in cardiomyocytes.

Abstract

BACKGROUND:

Angiotensin II (Ang II) in the local cardiac renin-angiotensin system (RAS) is closely associated with alcoholic cardiomyopathy (ACM). Inhibition of local cardiac RAS has great significance in the treatment of ACM. Although aldehyde dehydrogenase 2 (ALDH2) has been demonstrated to protect against ACM through detoxification of aldehydes, the precise mechanisms are largely unknown. In the present study, we determined whether ALDH2 improved cardiac damage by inhibiting the local RAS in ACM and investigated the related regulatory mechanisms.

METHODS AND RESULTS:

Adult male mice were fed with 5% ethanol or a control diet for 2months, with or without the ALDH2 activator Alda-1. Heavy ethanol consumption induced cardiac damage, increased angiotensinogen (AGT) and Ang II and decreased myocardial ALDH2 activity in hearts. ALDH2 activation improved ethanol-induced cardiac damage and decreased AGT and Ang II in hearts. In vitro, ALDH2 activation or overexpression decreased AGT and Ang II in cultured cardiomyocytes treated with 400mmol/L ethanol for 24h. Furthermore, p38 MAP kinase (p38 MAPK)/cyclic adenosine monophosphate response element-binding protein (CREB) pathway activation by ethanol increased AGT and Ang II in cardiomyocytes. In addition, ALDH2 activation or overexpression inhibited the p38 MAPK/CREB pathway leading to decreased AGT and Ang II in cardiomyocytes. We also found that p38 MAPK activation effectively mitigated Alda-1-decreased AGT and Ang II, the effect of which was reversed by inhibition of CREB.

CONCLUSIONS:

ALDH2 decreased AGT and Ang II in the local cardiac RAS via inhibiting the p38 MAPK/CREB pathway in ACM, thus improving ethanol-induced cardiac damage.

• Authors: Baoshan Liu, Rui Zhang, Shujian Wei, Qiuhuan Yuan, Mengyang Xue, Panpan Hao, Feng Xu, Jiali Wang, Yuguo Chen
• Journal: International journal of cardiology (Int J Cardiol) Vol. 257 Pg. 150-159 (04 15 2018) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 29506687 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Cardiotonic Agents
• Creb1 protein, mouse
• Cyclic AMP Response Element-Binding Protein
• Angiotensinogen
• Angiotensin II
• ALDH2 protein, mouse
• Aldehyde Dehydrogenase, Mitochondrial

Topics

• Adenoviridae (genetics)
• Aldehyde Dehydrogenase, Mitochondrial (administration & dosage, genetics, metabolism)
• Angiotensin II (metabolism)
• Angiotensinogen (antagonists & inhibitors, metabolism)
• Animals
• Animals, Newborn
• Cardiomyopathy, Alcoholic (metabolism, prevention & control)
• Cardiotonic Agents (administration & dosage, metabolism)
• Cells, Cultured
• Cyclic AMP Response Element-Binding Protein (antagonists & inhibitors, metabolism)
• Genetic Vectors (administration & dosage, genetics)
• MAP Kinase Signaling System (drug effects, physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Myocytes, Cardiac (drug effects, metabolism)
• Rats
• Rats, Wistar
• Renin-Angiotensin System (drug effects, physiology)