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.
Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, Hunan Province, China.
Biomed Pharmacother. 2023 Sep;165:115195. doi: 10.1016/j.biopha.2023.115195. Epub 2023 Jul 27.
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 HS 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.
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 CoCl. Western blot, RT-PCR, transmission electron microscopy, immunohistochemistry, as well as echocardiography, and studies on isolated hearts were employed.
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.
The mitochondrial-targeted HS 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.
研究揭示了线粒体自噬和铁死亡参与了心肌纤维化的发病机制。本研究旨在探讨线粒体靶向 HS 供体 AP39 是否通过 PINK1/Parkin 通路抑制线粒体自噬并拮抗心肌细胞铁死亡，从而改善心肌梗死后大鼠的心肌纤维化。
通过腹腔注射大剂量异丙肾上腺素建立大鼠心肌梗死模型，用 CoCl2 诱导 H9c2 心肌细胞缺氧损伤。采用 Western blot、RT-PCR、透射电镜、免疫组化及离体心脏实验等方法。
在心肌梗死大鼠的心脏中，间质胶原纤维明显堆积，同时 CSE 蛋白表达下调，PINK1/Parkin 信号通路被激活，线粒体自噬被激活。AP39 干预后，上述变化明显改善，加入 PAG 可逆转这一作用。在体外实验中也观察到了类似的结果。此外，加入 CCCP 逆转了 AP39 对心肌细胞铁死亡的拮抗作用，而加入 RSL3 则逆转了 AP39 对心肌细胞胶原产生的抑制作用。
线粒体靶向 HS 供体 AP39 可通过 PINK1/Parkin 通路抑制线粒体自噬，拮抗心肌细胞铁死亡，改善心肌梗死后大鼠的心肌纤维化。
