title: TM-1-1DP exerts protective effect against myocardial ischemia reperfusion injury via AKT-eNOS pathway.
abstract: 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.
authors: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Hui-Chun
authors: HC
authors: Ku
authors: Shih-Yi
authors: SY
authors: Lee
authors: Chi-Hsuan
authors: CH
authors: Chen
authors: Yao-Hsing
authors: YH
authors: Wang
authors: Chin-Ting
authors: CT
authors: Lin
authors: Shoei-Sheng
authors: SS
authors: Lee
authors: Ting-Hsuan
authors: TH
authors: Li
authors: Ming-Jai
authors: MJ
authors: Su
mesh_terms: D000818:Animals; D001060:Aporphines / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006334:Heart Function Tests; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C000604223:1,10-dimethoxy-6-(2-(2-methoxyphenoxy)ethyl)-5,6,6a,7-tetrahydro-4H-dibenzol(de,g)quinoline-2,9-diy1 bis(dihydrogen phosphate); D001060:Aporphines; D002316:Cardiotonic Agents; D017382:Reactive Oxygen Species; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051057:Proto-Oncogene Proteins c-akt