A Novel Danshensu-Tetramethylpyrazine Conjugate DT-010 Provides Cardioprotection through the PGC-1α/Nrf2/HO-1 Pathway

• Published in: Biological & pharmaceutical bulletin Vol. 40; no. 9; pp. 1490 - 1498
• Main Authors: Zhang, Xiaojing, Hu, Huihui, Luo, Jingxiong, Deng, Huixing, Yu, Pei, Zhang, Zaijun, Zhang, Gaoxiao, Shan, Luchen, Wang, Yuqiang
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.09.2017; Japan Science and Technology Agency
• Subjects: Animals; Apoptosis; Cardiovascular diseases; Cell Line; Cell Survival; Danshensu derivative; Free radicals; Free Radicals - metabolism; Heme; Heme oxygenase (decyclizing); Heme Oxygenase-1 - metabolism; Hydroxyl radicals; Hypoxia; Iodoacetic Acid; Ischemia; Lactates - pharmacology; Lactates - therapeutic use; Ligusticum; Male; Mitochondria; Myocardial infarction; Myocardial Infarction - etiology; Myocardial Infarction - metabolism; Myocardial Infarction - prevention & control; Myocardial ischemia; Myocardial Ischemia - complications; Myocardial Ischemia - drug therapy; Myocardial Ischemia - metabolism; Myocardial Ischemia - pathology; myocardial ischemia reperfusion injury; Myocardium - cytology; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; NF-E2-Related Factor 2 - metabolism; Nuclear transport; Oxidation; oxidative stress; Oxygenase; peroxisome proliferator-activated receptor gamma coactivator 1 alpha/nuclear factor-E2-related factor 2/heme oxygenase-1 (PGC-1α/Nrf2/HO-1) pathway; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Peroxynitrite; Phytotherapy; Plant Extracts - pharmacology; Plant Extracts - therapeutic use; Pyrazines - pharmacology; Pyrazines - therapeutic use; Rats; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Rodents; Salvia miltiorrhiza; Superoxide; tert-Butylhydroperoxide; Translocation; Up-Regulation; apoptosis; peroxisome proliferator-activated receptor gamma coactivator 1 alpha/nuclear factor-E2-related factor 2/heme oxygenase-1 (PGC-1α/Nrf2/HO-1) pathway; oxidative stress; myocardial ischemia reperfusion injury; Danshensu derivative
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b17-00313

In this study, we investigated the cardioprotective mechanisms of action of DT-010, a novel danshensu-tetramethylpyrazine conjugate. DT-010 significantly preserved cell viability and suppressed cell apoptosis in H9c2 cells injured by tert-butylhydroperoxide (t-BHP), iodoacetic acid (IAA) and hypoxia-reoxygenation. In addition, DT-010 pre-treatment reduced the intracellular level of free radicals including superoxide anion (·O2−), hydroxyl radical (·OH) and peroxynitrite anion (ONOO−) after t-BHP exposure. Moreover, DT-010 up-regulated the protein expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and nuclear factor-E2-related factor 2 (Nrf2) as well as mitochondrial transcription factor A (Tfam) and heme oxygenase-1 (HO-1) in H9c2 cells. DT-010 also triggered Nrf2 nuclear translocation. In a rat myocardial ischemia-reperfusion model, DT-010 significantly alleviated myocardial infarction. The results indicated that DT-010 may be a promising candidate for the treatment of cardiovascular diseases, particularly myocardial ischemia and reperfusion injury.