Department of Emergency Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing, China.
Department of Emergency Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing, China.
Arch Biochem Biophys. 2024 Feb;752:109855. doi: 10.1016/j.abb.2023.109855. Epub 2023 Dec 13.
Sepsis-induced cardiomyopathy (SIC), caused by a dysregulated host response to infection, is a major contributor to high mortality. Angiotensin-converting enzyme 2 (ACE2), a crucial component of the renin-angiotensin system (RAS), has protective effects against several cardiovascular diseases, such as myocardial infarction and heart failure. However, the role of ACE2 in the pathogenesis of SIC and underlying mechanisms remain unknown. The present study was designed to examine the effects of ACE2 activation or inhibition on SIC in C57BL/6 mice. The ACE2 activator diminazene aceturate (DIZE) and ACE2 inhibitor MLN-4760 were applied for treatment. Myocardial function, inflammatory response, oxidative stress, apoptosis and mitochondrial biogenesis were investigated. Major assays were echocardiography, H&E staining, immunofluorescence staining, DHE staining, TUNEL staining, Western blot, qPCR analysis, ELISA and corresponding kits. We confirmed that ACE2 was markedly downregulated in septic heart tissues. Pharmacological activation of ACE2 by DIZE ameliorated cecal ligation puncture (CLP)-induced mortality, cardiac dysfunction, inflammatory response, oxidative stress and the cardiomyocyte apoptosis by promoting MasR-Sirt1-mediated mitochondrial biogenesis. In contrast, SIC was aggravated via inhibiting MasR-Sirt1-mediated mitochondrial biogenesis by the use of ACE2 inhibitor MLN-4760. Consequently, activation of ACE2 may protect against SIC by promoting MasR-Sirt1-mediated mitochondrial biogenesis.
脓毒症性心肌病（SIC）是由宿主对感染的失调反应引起的，是导致高死亡率的主要因素。血管紧张素转换酶 2（ACE2）是肾素-血管紧张素系统（RAS）的重要组成部分，对多种心血管疾病具有保护作用，如心肌梗死和心力衰竭。然而，ACE2 在 SIC 的发病机制中的作用及其潜在机制尚不清楚。本研究旨在研究 ACE2 激活或抑制对 C57BL/6 小鼠 SIC 的影响。应用 ACE2 激活剂地昔尼尔（DIZE）和 ACE2 抑制剂 MLN-4760 进行治疗。研究了心肌功能、炎症反应、氧化应激、细胞凋亡和线粒体生物发生。主要检测方法包括超声心动图、H&E 染色、免疫荧光染色、DHE 染色、TUNEL 染色、Western blot、qPCR 分析、ELISA 和相应试剂盒。我们证实 ACE2 在脓毒症心脏组织中明显下调。通过 DIZE 对 ACE2 的药理学激活，通过促进 MasR-Sirt1 介导的线粒体生物发生，改善了盲肠结扎穿刺（CLP）诱导的死亡率、心脏功能障碍、炎症反应、氧化应激和心肌细胞凋亡。相反，通过使用 ACE2 抑制剂 MLN-4760 抑制 MasR-Sirt1 介导的线粒体生物发生，加重了 SIC。因此，ACE2 的激活可能通过促进 MasR-Sirt1 介导的线粒体生物发生来保护 SIC。
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