Abstract：
Mitochondrial dysfunction and the activation of multiple programmed cell death (PCD) have been shown to aggravate the severity and mortality associated with the progression of myocardial infarction (MI). Although pharmacological modulation of mitochondrial dynamics, including treatment with the fusion promoter (M1) and the fission inhibitor (Mdivi-1), exerted cardioprotection against several cardiac complications, their roles in the post-MI model have never been investigated. Using a MI rat model instigated by permanent left-anterior descending (LAD) coronary artery occlusion, post-MI rats were randomly assigned to receive one of 4 treatments (n = 10/group): vehicle (DMSO 3%V/V), enalapril (10 mg/kg), Mdivi-1 (1.2 mg/kg) and M1 (2 mg/kg), while a control group of sham operated rats underwent surgery without LAD occlusion (n = 10). After 32-day treatment, cardiac and mitochondrial function, and histopathological morphology were investigated and molecular analysis was performed. Treatment with enalapril, Mdivi-1, and M1 significantly mitigated cardiac pathological remodeling, reduced myocardial injury, and improved left ventricular (LV) function in post-MI rats. Importantly, all interventions also attenuated mitochondrial dynamic imbalance and mitigated activation of apoptosis, necroptosis, and pyroptosis after MI. This investigation demonstrated for the first time that chronic mitochondrial dynamic-targeted therapy mitigated mitochondrial dysfunction and activation of PCD, leading to improved LV function in post-MI rats.
摘要：
线粒体功能障碍和多种程序性细胞死亡（PCD）的激活已被证明会加重与心肌梗死（MI）进展相关的严重程度和死亡率。虽然线粒体动力学的药理学调节，包括用融合启动子（M1）和裂变抑制剂（Mdivi-1）处理，对几种心脏并发症发挥心脏保护作用，他们在MI后模型中的角色从未被调查过。使用永久性左前降支（LAD）冠状动脉闭塞引起的MI大鼠模型，MI后大鼠被随机分配接受4种治疗之一（n=10/组）：载体（DMSO3％V/V），依那普利（10mg/kg），Mdivi-1（1.2mg/kg）和M1（2mg/kg），而对照组的假手术大鼠接受了没有LAD闭塞的手术（n=10）。经过32天的治疗，心脏和线粒体功能，和组织病理学形态进行了研究和分子分析。用依那普利治疗，Mdivi-1和M1可显着减轻心脏病理重塑，减少心肌损伤，并改善MI后大鼠的左心室（LV）功能。重要的是,所有干预措施也减轻了线粒体动态失衡，减轻了细胞凋亡的激活，坏死,MI后的焦亡。这项研究首次表明，慢性线粒体动态靶向治疗减轻了线粒体功能障碍和PCD的激活。改善MI后大鼠的LV功能。
