Hwa Mei Hospital, University of Chinese Academy of Sciences, No.41, Northwest Street, Ningbo, 315010, Zhejiang, China; Ningxia Medical University, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China.
Emergency and Critical Care Center, Renmin Hospital, Hubei University of Medicine, No.37 Chaoyang Middle Road, Shiyan, 442000, Hubei, China.
Eur J Pharmacol. 2022 Jul 15;927:175038. doi: 10.1016/j.ejphar.2022.175038. Epub 2022 May 20.
Mitochondrial dysfunction plays a significant role in the development of postresuscitation myocardial dysfunction (PRMD). Endogenous carbon monoxide (CO) has obvious protective effects on cardiomyocytes and that mitochondria are considered to be the main targets of CO action. This study aimed to investigate whether exogenous CO (carbon monoxide releasing molecule 2, CORM-2) could protect against PRMD, and improve cardiac function in rats via the mitochondria pathway. Forty male Sprague-Dawley rats were randomly divided into five groups: sham group, model cardiopulmonary resuscitation (CPR) group, CORM-2 treatment group, inactivated CORM-2 group, and DMSO (Dimethyl sulfoxide, CORM-2 vehicle) group. Excluding the sham group, all groups underwent CPR 4 min after cardiac arrest (CA), animals in every group underwent surgery for catheter insertion before the CA-CPR. In the treatment groups, CORM-2 and inactivated CORM-2 (both 4 mg/kg, dissolved in 2% dimethyl sulfoxide and diluted in normal saline) were intraperitoneally injected 12 h before CPR was started. In the sham, model CPR, and vehicle groups, animals were administered normal saline or vehicle as appropriate. The results demonstrated that the mitochondrial ultrastructure abnormalities in CORM-2 group was less severe than CPR rats. CORM-2 alleviated myocardial contractile and diastolic dysfunction after CPR, decreased caspase-3 and caspase-9 expression in myocardial tissues, and meanwhile suppressed cytochrome c release from mitochondria. Furthermore, CORM-2 lessen the production of reactive oxygen species (ROS) and increased myocardial mitochondrial respiratory complex IV enzyme activity after CPR. Dynamin-related protein 1（Drp1) was significantly less expressed in CORM-2 group with high expression of mitofusion-2 (Mfn2), suggesting that CORM-2 can promote mitochondrial fusion and reduce mitochondrial fission. Collectively, we provide the evidence that CORM-2 effectively relieved myocardial injury after CPR in rats, protected myocardial mitochondria, and preserved cardiac function after resuscitation. The proposed mechanisms of action were improved mitochondrial respiratory function, maintained mitochondrial dynamics balance, and suppressed the mitochondrial-mediated apoptosis.
线粒体功能障碍在心脏骤停后心肌功能障碍（PRMD）的发展中起着重要作用。内源性一氧化碳（CO）对心肌细胞有明显的保护作用，而线粒体被认为是 CO 作用的主要靶点。本研究旨在探讨外源性 CO（一氧化碳释放分子 2，CORM-2）是否可以通过线粒体途径保护心脏骤停后大鼠的心肌，改善心脏功能。
将 40 只雄性 Sprague-Dawley 大鼠随机分为 5 组：假手术组、模型心肺复苏（CPR）组、CORM-2 治疗组、失活 CORM-2 组和 DMSO（二甲基亚砜，CORM-2 载体）组。除假手术组外，所有组在心脏骤停（CA）后 4 分钟进行 CPR，每组动物在 CA-CPR 前进行导管插入术。在治疗组中，CORM-2 和失活 CORM-2（均为 4mg/kg，溶于 2%二甲基亚砜并稀释于生理盐水）在 CPR 开始前 12 小时腹腔内注射。在假手术、模型 CPR 和载体组中，动物给予适当的生理盐水或载体。
结果表明，CORM-2 组的线粒体超微结构异常比 CPR 大鼠轻。CORM-2 减轻 CPR 后心肌收缩和舒张功能障碍，降低心肌组织中 caspase-3 和 caspase-9 的表达，同时抑制细胞色素 c 从线粒体释放。此外，CORM-2 减少 CPR 后活性氧（ROS）的产生，并增加心肌线粒体呼吸复合物 IV 酶活性。CPR 后 CORM-2 组 dynamin-related protein 1（Drp1）表达明显减少，mitofusion-2（Mfn2）表达升高，提示 CORM-2 可促进线粒体融合，减少线粒体裂变。
总之，我们提供了 CORM-2 有效缓解大鼠 CPR 后心肌损伤、保护心肌线粒体和维持复苏后心功能的证据。提出的作用机制是改善线粒体呼吸功能、维持线粒体动力学平衡和抑制线粒体介导的细胞凋亡。
