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

Affiliation
Institute of Basic Theory for Chinese Medicine ,China Academy of Chinese Medical Sciences ,Beijing ,China
Zhang, Fangyuan;
Affiliation
School of Acupuncture and Tuina ,School of Regimen and Rehabilitation ,Nanjing University of Chinese Medicine ,Nanjing ,China
Li, Ziyun;
Affiliation
Affiliated Hospital of Integrated Traditional Chinese and Western Medicine ,Nanjing University of Chinese Medicine ,Nanjing ,China
Gao, Ping;
Affiliation
School·of·Basic·Medical·Sciences Chengdu·University·of Traditional·Chinese Medicine ,Chengdu ,China
Zou, Jiaxi;
Affiliation
College of Chinese Medicine ,Changchun University of Chinese Medicine ,Changchun ,Jilin ,China
Cui, Yuting;
Affiliation
The Third School of Clinical Medicine ,Nanjing University of Chinese Medicine ,Nanjing ,China
Qian, Yi;
Affiliation
School of Chinese Medicine ,School of Integrated Chinese and Western Medicine ,Nanjing University of Chinese Medicine ,Nanjing ,China
Gu, Renjun;
Affiliation
China Science and Technology Development Center for Chinese Medicine ,Beijing ,China
Xu, Weiming;
Affiliation
Institute of Basic Theory for Chinese Medicine ,China Academy of Chinese Medical Sciences ,Beijing ,China
Hu, Jingqing

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.

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License Holder: Copyright © 2022 Zhang, Li, Gao, Zou, Cui, Qian, Gu, Xu and Hu.

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