2. Academic Validation
  3. AP39 inhibits ferroptosis by inhibiting mitochondrial autophagy through the PINK1/parkin pathway to improve myocardial fibrosis with myocardial infarction

AP39 inhibits ferroptosis by inhibiting mitochondrial autophagy through the PINK1/parkin pathway to improve myocardial fibrosis with myocardial infarction

  • Biomed Pharmacother. 2023 Jul 27;165:115195. doi: 10.1016/j.biopha.2023.115195.
Ting Yang 1,  Qi Yang 2,  Qi Lai 1,  Junxiong Zhao 2,  Liangui Nie 2,  Shengquan Liu 2,  Jun Yang 3,  Chun Chu 4
Affiliations

Affiliations

  • 1 Department of Pharmacy, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, Hunan Province, China; School of Pharmaceutical Science of University of South China, Hengyang 421000, Hunan Province, China.
  • 2 Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, Hunan Province, China.
  • 3 Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, Hunan Province, China. Electronic address: [email protected].
  • 4 Department of Pharmacy, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, Hunan Province, China. Electronic address: [email protected].
PMID: 37516015 DOI: 10.1016/j.biopha.2023.115195
Abstract

Background and purpose: Research has revealed the involvement of mitochondrial Autophagy and iron death in the pathogenesis of myocardial fibrosis. The objective of this study is to investigate whether the mitochondrial-targeted H2S donor AP39 inhibits mitochondrial Autophagy and antagonizes myocardial cell iron death through the PINK1/Parkin pathway, thereby improving myocardial fibrosis in rats with myocardial infarction.

Experimental approach: A rat model of myocardial infarction was created by intraperitoneal injection of a high dose of isoproterenol, and H9c2 myocardial cells were subjected to hypoxic injury induced by CoCl2. Western blot, RT-PCR, transmission electron microscopy, immunohistochemistry, as well as echocardiography, and studies on isolated hearts were employed.

Key results: In the hearts of rats with myocardial infarction, there was a significant accumulation of interstitial collagen fibers, accompanied by downregulation of CSE protein expression, activation of the PINK1/Parkin signaling pathway, and activation of mitochondrial Autophagy. Intervention with AP39 resulted in a significant improvement of the aforementioned changes, which could be reversed by the addition of PAG. Similar results were observed in vitro experiments. Furthermore, the addition of CCCP reversed the antagonistic effect of AP39 on myocardial cell iron death, while the addition of RSL3 reversed the inhibitory effect of AP39 on collagen production in myocardial cells.

Conclusion and implications: The mitochondrial-targeted H2S donor AP39 can inhibit mitochondrial Autophagy through the PINK1/Parkin pathway, antagonize myocardial cell iron death, and improve myocardial fibrosis in rats with myocardial infarction.

Keywords

AP39; Ferroptosis; Hydrogen sulfide; Mitochondrial autophagy; Myocardial fibrosis; Myocardial infarction.

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