TM-1-1DP exerts protective effect against myocardial ischemia reperfusion injury via AKT-eNOS pathway.

Coronary heart disease remains a leading cause of death in the world. The demand on targeting therapy to reduce myocardial ischemia/reperfusion (I/R) injury is still urgent. The pathogenesis of I/R-induced myocardial injury is complicated. Reactive oxygen species (ROS) generation and inflammatory response activation participate in the development of I/R injury. Cell death occurs and finally leads to myocardial infarction. A newly phenolic aporphine alkaloid derivative, TM-1-1DP, was synthesized in our team. We aimed to investigate the effect of novel compound on myocardial I/R injury. Rats were subjected to 1-h coronary artery occlusion and followed by 2-h reperfusion. Adult rat cardimoycyte was isolated for the cell study, and H2O2 was added into culture medium to induce ROS stress. As compared to the sham group, TM-1-1DP-treated rats had better cardiac performance in association with less infarct size and cardiac injury markers after myocardial I/R. The protective effect is associated with the inhibition of inflammatory response, cell death-related pathway (caspase-3 and TNF-α), and the activation of AKT-eNOS pathway. The finding was further coincided with the cell study. TM-1-1DP treatment significantly alleviated ROS production and improved cell viability in cardiomyocyte after H2O2 exposure. The action of TM-1-1DP is via a nitric oxide (NO)-dependent manner, since NOS inhibitor, L-NAME, abolished the protective effect. We provide a new insight into this therapeutic potential for phenolic aporphine alkaloid in myocardial I/R.