Zinc-Induced SUMOylation of Dynamin-Related Protein 1 Protects the Heart against Ischemia-Reperfusion Injury

Abstract

Background. Zinc plays a role in mitophagy and protects cardiomyocytes from ischemia/reperfusion injury. This study is aimed at investigating whether SUMOylation of Drp1 is involved in the protection of zinc ion on cardiac I/R injury. Methods. Mouse hearts were subjected to 30 minutes of regional ischemia followed by 2 hours of reperfusion (ischemia/reoxygenation (I/R)). Infarct size and apoptosis were assessed. HL-1 cells were subjected to 24 hours of hypoxia and 6 hours of reoxygenation (hypoxia/reoxygenation (H/R)). Zinc was given 5 min before reperfusion for 30 min. SENP2 overexpression plasmid (Flag-SENP2), Drp1 mutation plasmid (Myc-Drp1 4KR), and SUMO1 siRNA were transfected into HL-1 cells for 48 h before hypoxia. Effects of zinc on SUMO family members were analyzed by Western blotting. SUMOylation of Drp1, apoptosis and the collapse of mitochondrial membrane potential (ΔΨm), and mitophagy were evaluated. Results. Compared with the control, SUMO1 modification level of proteins in the H/R decreased, while this effect was reversed by zinc. In the setting of H/R, zinc attenuated myocardial apoptosis, which was reversed by SUMO1 siRNA. Similar effects were observed in SUMO1 KO mice exposed to H/R. In addition, the dynamin-related protein 1 (Drp1) is a target protein of SUMO1. The SUMOylation of Drp1 induced by zinc regulated mitophagy and contributed to the protective effect of zinc on H/R injury. Conclusions. SUMOylation of Drp1 played an essential role in zinc-induced cardio protection against I/R injury. Our findings provide a promising therapeutic approach for acute myocardial I/R injury.

RETRACTED: Oxidized LDL Causes Endothelial Apoptosis by Inhibiting Mitochondrial Fusion and Mitochondria Autophagy

“…Mitophagy is a process involving impaired mitochondrial degradation through lysosomes (Bi et al, 2019;Hsieh et al, 2019;Tian et al, 2019). Mitochondrial fusion is an alteration of mitochondrial morphology through the fusion of two mitochondria (Bian et al, 2019). The protective effects of mitophagy and mitochondrial fusion on cardiovascular FIGURE 5 | Overexpression of Opa1 restores endothelial cell viability and reduces apoptosis after ox-LDL treatment by modulating mitophagy and mitochondrial fusion.…”

[Retracted] The Role of Posttranslational Modification and Mitochondrial Quality Control in Cardiovascular Diseases

“…Previous research indicated that following I/R injury of the heart, the binding capacity of SUMO1 to Drp1 increased and formed a complex. Zinc promoted mitochondrial fission by increasing the acidification of the complex, thereby eliminating damaged mitochondria and maintaining mitochondrial quality stability, further improving cardiac function [ 43 ]. Evidence revealed that SENP3, an enzyme of deSUMOylation, was associated with apoptosis induction in response to cardiac I/R by affecting Drp1 localization in the mitochondria.…”

SUMOylation as a Therapeutic Target for Myocardial Infarction

“…The existing clinical therapies do not fully resolve MI/R injury in patients with coronary heart disease. (80).…”