Carbon monoxide-releasing molecule-2 ameliorates postresuscitation myocardial dysfunction in rat via mitochondrial-mediated apoptosis pathway and the regulation of mitochondrial dynamics

Abstract

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.