A Novel Danshensu-Tetramethylpyrazine Conjugate Dt-018 Provides Cardioprotection By Preserving Mitochondrial Function Through The Mef2d/Pgc-1 Alpha Pathway

In this work, we explored the protective effect of DT-018, a danshensu and tetramethylpyrazine conjugate, on mitochondrial injury induced by tert-butylhydroperoxide (t-BHP) and its possible mechanisms of action. DT-018 effectively quenched intracellular and mitochondrial reactive oxygen species (ROS), preserved the mitochondrial function, restored the intracellular level of ATP and augmented mitochondrial membrane potential (Delta Psi m) while suppressed mitochondrial swelling in isolated myocardial mitochondria. DT-018 increased the expression of MEF2D and PGC-1 alpha as well as Nrf2 and Tfam in H9c2 cells. Transfection of MEF2D-siRNA and PGC-1 alpha-siRNA down-regulated the protein expression of PGC-1 alpha and partially abolished the cardioprotection of DT-018 in t-BHP injured cells. For the in vivo studies, administration of DT-018 significantly alleviated infarct area induced by ischemia and reperfusion injury. These observations demonstrated that the cardioprotective effect of DT-018 is mediated, at least in part, by preservation of mitochondrial integrity through up-regulation of MEF2D/PGC-1 alpha pathway.