• Rifeng Gao, Kun Yang, Shiguan Le, Hanchuan Chen, Xiaolei Sun, Zhen Dong, Pingjin Gao, Xilu Wang, Jiaran Shi, Yanan Qu, Xiang Wei, Kai Hu, Jiucun Wang, Li Jin, Yi Li, Junbo Ge, and Aijun Sun.
• Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cardiac Surgery, The Second Affiliated Hospital, Zhejiang University, Hangzhou, China; Department of Cardiology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
• Transl Res. 2024 May 1; 267: 253825-38.

AbstractHigh-altitude heart disease (HAHD) is a complex pathophysiological condition related to systemic hypobaric hypoxia in response to transitioning to high altitude. Hypoxia can cause myocardial metabolic dysregulation, leading to an increased risk of heart failure and sudden cardiac death. Aldehyde dehydrogenase 2 (ALDH2) could regulate myocardial energy metabolism and plays a protective role in various cardiovascular diseases. This study aims to determine the effects of plateau hypoxia (PH) on cardiac metabolism and function, investigate the associated role of ALDH2, and explore potential therapeutic targets. We discovered that PH significantly reduced survival rate and cardiac function. These effects were exacerbated by ALDH2 deficiency. PH also caused a shift in the myocardial fuel source from fatty acids to glucose; ALDH2 deficiency impaired this adaptive metabolic shift. Untargeted/targeted metabolomics and transmission electron microscopy revealed that ALDH2 deficiency promoted myocardial fatty-acid deposition, leading to enhanced fatty-acid transport, lipotoxicity and mitochondrial dysfunction. Furthermore, results showed that ALDH2 attenuated PH-induced impairment of adaptive metabolic programs through 4-HNE/CPT1 signaling, and the CPT1 inhibitor etomoxir significantly ameliorated ALDH2 deficiency-induced cardiac impairment and improved survival in PH mice. Together, our data reveal ALDH2 acts as a key cardiometabolic adaptation regulator in response to PH. CPT1 inhibitor, etomoxir, may attenuate ALDH2 deficiency-induced effects and improved cardiac function in response to PH.Copyright © 2024 Elsevier Inc. All rights reserved.

19 keywords...

hide…