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

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

doi:10.3389/fphar.2020.01083

Astragaloside IV Derivative (LS-102) Alleviated Myocardial Ischemia Reperfusion Injury by Inhibiting Drp1^Ser616 Phosphorylation-Mediated Mitochondrial Fission

Front Pharmacol. 2020 Sep 17:11:1083. doi: 10.3389/fphar.2020.01083. eCollection 2020.

Authors

Li Chen^{1

2}, Xiao-Yi Chen¹, Qian-Long Wang¹, Si-Jin Yang², Hua Zhou¹, Li-Sheng Ding³, Lin-Sen Qing³, Pei Luo¹

Affiliations

¹ State Key Laboratories for Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China.
² Department of Cardiac Encephalopathy, Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou, China.
³ Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.

Abstract

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^Ser616) and increasing the phosphorylation of Drp1 at Ser637 (Drp1^Ser637) in H9c2 cells. Importantly, we also robustly confirmed Drp1^Ser616 as a novel GSK-3β phosphorylation site. GSK-3β-mediated phosphorylation at Drp1^Ser616 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.

Keywords: Drp1 phosphorylation; GSK-3β; astragalosidic acid; mitochondrial fission; myocardial ischemia reperfusion.