Aldehyde dehydrogenase 2 protects against sympathetic excitation-induced cardiac fibrosis.

Abstract

Sympathetic stimulated-cardiac fibrosis imposes great significance on both disease progression and survival in the pathogenesis of many cardiovascular diseases. However, there are few effective therapies targeting it clinically. The cardioprotective effect of aldehyde dehydrogenase 2 (ALDH2) has been explored in many pathological conditions, whether it can exert benefit effects on chronic sympathetic stimulus-induced cardiac fibrosis remains unclear. In this study, we determined to explore the role of ALDH2 on isoproterenol (ISO)-induced cardiac fibroblasts (CF) proliferation and cardiac fibrosis. It was found that ALDH2 enzymatic activity was impaired in ISO-induced HCF proliferation and Aldh2 deficiency promoted mouse CF proliferation. Alda-1, an ALDH2 activator, exerted obvious suppressive effect on ISO-induced HCF proliferation, together with the induction of cell cycle arrest at G0/G1 phase and decreased expression of cyclin E1 and cyclin-dependent kinase 2 (CDK2). Mechanistically, the inhibitory role of Alda-1 on HCF proliferation was achieved by decreasing mitochondrial reactive oxygen species (ROS) production, which was partially reversed by rotenone, an inducer of ROS. In addition, wild-type mice treated with Alda-1 manifested with reduced fibrosis and better cardiac function after ISO pump. In summary, Alda-1 alleviates sympathetic excitation-induced cardiac fibrosis via decreasing mitochondrial ROS accumulation, highlighting ALDH2 activity as a promising drug target of cardiac fibrosis.

• Authors: Qiuhuan Yuan, Feihong Yang, Shuai Dai, Zheng Wang, Youshun Xu, Bai-Chao Xu, Yi Sun, Boyuan Zheng, Yu Zhao, Wenjun Wang, Baoshan Liu, Jiali Wang, Sumei Cui, Shengchuan Cao, Rui Zhang, Li Xue, Shujian Wei, Mengyang Xue, Tonghui Xu, Feng Xu, Yuguo Chen
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 533 Issue 4 Pg. 1427-1434 (12 17 2020) ISSN: 1090-2104 [Electronic] United States
• PMID: 33333711 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Benzamides
• Benzodioxoles
• Cardiotonic Agents
• N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide
• Reactive Oxygen Species
• ALDH2 protein, human
• ALDH2 protein, mouse
• Aldehyde Dehydrogenase, Mitochondrial
• Isoproterenol

Topics

• Aldehyde Dehydrogenase, Mitochondrial (antagonists & inhibitors, genetics, metabolism)
• Animals
• Benzamides (pharmacology)
• Benzodioxoles (pharmacology)
• Cardiomyopathies (chemically induced, enzymology, pathology)
• Cardiotonic Agents (pharmacology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Electrocardiography
• Fibroblasts (pathology)
• Fibrosis
• Heart Ventricles (pathology)
• Humans
• Isoproterenol (toxicity)
• Male
• Mice, Inbred C57BL
• Reactive Oxygen Species (metabolism)