Cardioprotection of a Novel Danshensu Derivate Against Oxidative Injury and Mitochondrial Dysfunction in Vitro and Myocardial Ischemia/Reperfusion Injury in Rat

Objectives Myocardial ischemia/reperfusion injury remains an important clinical problem in the world. Extensive research have focused on strategies for attenuating myocardial ischemia and reperfusion injury. Danshensu (DSS) and tetramethylpyrazine (TMP) are important cardioprotective components isolated from the traditional Chinese herbs Danshen and Chuanxiong, respectively. D2T is a novel conjugate with two molecules of DSS introduced to a TMP through an ester bond. This study aims to explore the cardioprotection of D2T and its mechanisms of action. Methods and Results H9c2 cardiomyocytes were treated with tert-butyl hydroperoxide(t-BHP) to induce oxidative stress in vitro. D2T pretreatment protected cardiomyocytes from t-BHP- induced oxidative injury and mitochondrial dysfunction. Western blot analysis showed that D2T activated phosphorylation of PI3K and Akt and induced HO-1 protein expression together with its upstream regulator Nrf2. Wortmannin, a phosphoinositide 3-kinase (PI3K) inhibitor, partially abolished the restoration of cell viability offered by D2T. In a rat myocardial ischemia and reperfusion model, intravenous D2T significantly reduced infarct size. Conclusions The cardioprotection of D2T is mediated by inhibiting oxidative injury and mitochondrial dysfunction. D2T acts by the activation of PI3k/Akt and Nrf2/HO-1 signaling pathways, suggesting D2T may be an effective treatment for myocardial ischemia/reperfusion injury.