A Novel Danshensu-Tetramethylpyrazine Conjugate DT-018 Provides Cardioprotection by Preserving Mitochondrial Function Through the MEF2D/PGC-1α Pathway

Title:A Novel Danshensu-Tetramethylpyrazine Conjugate DT-018 Provides Cardioprotection by Preserving Mitochondrial Function Through the MEF2D/PGC-1α Pathway

Volume: 23 Issue: 39

Author(s): Xiaojing Zhang, Jingxiong Luo, Yali Huang, Huixing Deng, Huihui Hu, Pei Yu, Yewei Sun*, Luchen Shan* Yuqiang Wang

Affiliation:

• Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Guangzhou 510632,China

• Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Guangzhou 510632,China

Keywords: Danshensu derivative, cardioprotection, mitochondrial function preservation, ischemia/reperfusion, MEF2D/PGC-1α pathway, reactive oxygen species (ROS.

Abstract: 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 (Δψm) while suppressed mitochondrial swelling in isolated myocardial mitochondria. DT-018 increased the expression of MEF2D and PGC-1α as well as Nrf2 and Tfam in H9c2 cells. Transfection of MEF2D-siRNA and PGC-1α-siRNA down-regulated the protein expression of PGC-1α 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-1α pathway.

Cite this article as:

Zhang Xiaojing , Luo Jingxiong , Huang Yali , Deng Huixing, Hu Huihui , Yu Pei , Sun Yewei *, Shan Luchen *, Wang Yuqiang , A Novel Danshensu-Tetramethylpyrazine Conjugate DT-018 Provides Cardioprotection by Preserving Mitochondrial Function Through the MEF2D/PGC-1α Pathway, Current Pharmaceutical Design 2017; 23 (39) . https://dx.doi.org/10.2174/1381612823666170817125925