AUTHOR=Chen Li , Chen Xiao-Yi , Wang Qian-Long , Yang Si-Jin , Zhou Hua , Ding Li-Sheng , Qing Lin-Sen , Luo Pei 

TITLE=Astragaloside IV Derivative (LS-102) Alleviated Myocardial Ischemia Reperfusion Injury by Inhibiting Drp1Ser616 Phosphorylation-Mediated Mitochondrial Fission

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.01083

DOI=10.3389/fphar.2020.01083

ISSN=1663-9812

ABSTRACT=<p>Our previous studies showed that Astragaloside IV derivative (LS-102) exhibited potent protective function against ischemia reperfusion (I/R) injury, but little is known about the mechanisms. Mitochondrial fission regulated by dynamin-related protein1 (Drp1) is a newly recognized determinant of mitochondrial function. This study aimed to investigate the protection of LS-102 on mitochondrial structure and function by regulating the activity of Drp1 using models of H9c2 cardiomyocyte injury induced by hypoxia-reperfusion (H/R), and rat heart injury induced by I/R. The results showed that LS-102 significantly decreased apoptosis, levels of ROS, CK, LDH, and calcium, upregulating MMP, and the Bax/Bcl-2 ratio in cardiomyocytes during I/R injury. Furthermore, LS-102 prevented I/R-induced mitochondrial fission by decreasing Drp1’s mitochondrial localization through decreasing the phosphorylation of Drp1 at Ser616 (Drp1<sup>Ser616</sup>) and increasing the phosphorylation of Drp1 at Ser637 (Drp1<sup>Ser637</sup>) in H9c2 cells. Importantly, we also robustly confirmed Drp1<sup>Ser616</sup> as a novel GSK-3β phosphorylation site. GSK-3β-mediated phosphorylation at Drp1<sup>Ser616</sup> may be associated with mitochondrial fission during I/R of cardiomyocytes. In conclusion, LS-102 exerts cardio protection against I/R-induced injury by inhibiting mitochondrial fission via blocking GSK-3β-mediated phosphorylation at Ser616 of Drp1.</p>