Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Cell Signal. 2024 Aug;120:111219. doi: 10.1016/j.cellsig.2024.111219. Epub 2024 May 8.
Cardiac remodeling is a critical process following myocardial infarction (MI), potentially leading to heart failure if untreated. The significance of mitochondrial homeostasis in MI remains insufficiently understood. Samm50 is an essential component of mitochondria. Our study aimed to investigate its role in hypoxia-induced cardiac injury and the underlying mechanisms. First, we observed that Samm50 was dynamically downregulated in mice with MI compared to the control mice. In vitro, Samm50 was also downregulated in oxygen-glucose-deprived neonatal rat cardiomyocytes and fibroblasts. Overexpression and knockdown of Samm50 mitigated and exacerbated cardiac apoptosis and fibrosis, while also improving and worsening mitochondrial homeostasis, respectively. Protein interactions with Samm50 during the protective process were identified via immune-coprecipitation/mass spectroscopy. Mechanistically, serine hydroxymethyltransferase 2 (Shmt2) interacted with Samm50, acting as a crucial element in the protective process by hindering the transfer of Bax from the cytoplasm to the mitochondria and subsequent activation of caspase-3. Inhibition of Shmt2 diminished the protective effect of Samm50 overexpression against cardiac injury. Finally, Samm50 overexpression in vivo mitigated cardiac remodeling and enhanced cardiac function in both acute and chronic MI. In conclusion, Samm50 overexpression mitigated hypoxia-induced cardiac remodeling by inhibiting apoptosis and fibrosis, with Shmt2 acting as a key regulator in this protective process. The Samm50/Shmt2 axis represents a newly discovered mitochondria-related pathway for mitigating hypoxia-induced cardiac injury.
心肌重构是心肌梗死（MI）后的一个关键过程，如果不加以治疗，可能导致心力衰竭。线粒体动态平衡在 MI 中的意义仍未得到充分理解。Samm50 是线粒体的一个重要组成部分。我们的研究旨在探讨其在缺氧诱导的心脏损伤中的作用及其潜在机制。首先，我们观察到与对照组小鼠相比，MI 小鼠中的 Samm50 呈动态下调。在体外，缺氧剥夺培养的新生大鼠心肌细胞和成纤维细胞中 Samm50 也下调。Samm50 的过表达和敲低分别减轻和加重了心脏细胞凋亡和纤维化，同时分别改善和恶化了线粒体动态平衡。通过免疫沉淀/质谱鉴定 Samm50 在保护过程中的蛋白相互作用。在机制上，丝氨酸羟甲基转移酶 2（Shmt2）与 Samm50 相互作用，作为保护过程中的关键因素，通过阻止 Bax 从细胞质向线粒体转移以及随后的 caspase-3 激活来发挥作用。Shmt2 的抑制减弱了 Samm50 过表达对心脏损伤的保护作用。最后，体内 Samm50 的过表达减轻了急性和慢性 MI 中的心脏重构并增强了心脏功能。总之，Samm50 的过表达通过抑制细胞凋亡和纤维化减轻了缺氧诱导的心脏重构，Shmt2 是该保护过程中的关键调节因子。Samm50/Shmt2 轴代表了一种新发现的与线粒体相关的减轻缺氧诱导的心脏损伤的途径。
