HJ11 decoction restrains development of myocardial ischemia-reperfusion injury in rats by suppressing ACSL4-mediated ferroptosis

Fangyuan Zhang; Ziyun Li; Ping Gao; Jiaxi Zou; Yuting Cui; Yi Qian; Renjun Gu; Weiming Xu; Jingqing Hu

doi:10.3389/fphar.2022.1024292

HJ11 decoction restrains development of myocardial ischemia-reperfusion injury in rats by suppressing ACSL4-mediated ferroptosis

Front Pharmacol. 2022 Nov 22:13:1024292. doi: 10.3389/fphar.2022.1024292. eCollection 2022.

Authors

Fangyuan Zhang¹, Ziyun Li², Ping Gao³, Jiaxi Zou⁴, Yuting Cui⁵, Yi Qian⁶, Renjun Gu⁷, Weiming Xu^{8

9}, Jingqing Hu^{1

8}

Affiliations

¹ Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
² School of Acupuncture and Tuina, School of Regimen and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, China.
³ Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
⁴ School·of·Basic·Medical·Sciences Chengdu·University·of Traditional·Chinese Medicine, Chengdu, China.
⁵ College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China.
⁶ The Third School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
⁷ School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
⁸ China Science and Technology Development Center for Chinese Medicine, Beijing, China.
⁹ The First Affilliated Hospital of Henan University of CM, Zhengzhou, China.

Abstract

HJ11 is a novel traditional Chinese medicine developed from the appropriate addition and reduction of Si-Miao-Yong-An decoction, which has been commonly used to treat ischemia-reperfusion (I/R) injury in the clinical setting. However, the mechanism of action of HJ11 components remains unclear. Ferroptosis is a critical factor that promotes myocardial I/R injury, and the pathophysiological ferroptosis-mediated lipid peroxidation causes I/R injury. Therefore, this study explored whether HJ11 decoction ameliorates myocardial I/R injury by attenuating ACSL4-mediated ferroptosis. This study also explored the effect of ACSL4 expression on iron-dependent programmed cell death by preparing a rat model of myocardial I/R injury and oxygen glucose deprivation/reperfusion (OGD/R)-induced H9c2 cells. The results showed that HJ11 decoction improved cardiac function; attenuated I/R injury, apoptosis, oxidative stress, mitochondrial damage, and iron accumulation; and reduced infarct size in the myocardial I/R injury rat model. Additionally, HJ11 decoction suppressed the expression of ferroptosis-promoting proteins [Acyl-CoA synthetase long-chain family member 4 (ACSL4) and cyclooxygenase-2 (COX2)] but promoted the expression of ferroptosis-inhibiting proteins [ferritin heavy chain 1 (FTH1) and glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4)] in the myocardial tissues of the I/R injury rat model. Similar results were found with the OGD/R-induced H9c2 cells. Interestingly, ACSL4 knockdown attenuated iron accumulation, oxidative stress, and ferroptosis in the OGD/R-treated H9c2 cells. However, ACSL4 overexpression counteracted the inhibitory effect of the HJ11 decoction on OGD/R-triggered oxidative stress and ferroptosis in H9c2 cells. These findings suggest that HJ11 decoction restrained the development of myocardial I/R injury by regulating ACSL4-mediated ferroptosis. Thus, HJ11 decoction may be an effective medication to treat myocardial I/R injury.

Keywords: HJ11 decoction; cardiac function; ferroptosis; myocardial I/R injury; oxidative stress.