Resolvin D1 Inhibits Endothelial Permeability and Mitochondrial Damage Following Cardiac Ischemia–Reperfusion in Diabetic Mice

Abstract

Purpose Resolvin D1(RvD1), a metabolite derived from docosahexaenoic acid, plays important therapeutic roles in inflammatory diseases. However, the role of RvD1 in diabetic myocardial ischemia/reperfusion (IR) is still unknown. Methods Diabetic mice was established by high-fat diet and streptozotocin, RvD1 was pretreated by intraperitoneal injection for 3 days, followed by myocardial IR. To evaluate the effects of RvD1 on chronic cardiac remodeling, RvD1 was administered for another 2 weeks after IR. The effects of RvD1 following myocardial IR injury were measured, including severity of infarct size, regional inflammation, cardiac function, as well as permeability of cultured endothelial monolayer. Mitochondrial reactive oxygen species (mito-ROS) and mitochondrial membrane potential (MMP) were determined by MitoSOX and JC-1. Results RvD1 pretreatment significantly reduced infarct size and the content of Evans blue in injured heart, which was associated with decreased endothelial damage. RvD1 also reduced leukocyte density, gene expression of inflammatory cytokines, cardiomyocytes death, and mitochondrial damage compared to control group. At 2 weeks after myocardial IR, RvD1 treatment partially improved cardiac performance, and reduced cardiac fibrosis in diabetic IR. In vitro, RvD1 attenuated endothelial leakage induced by hypoxia-reoxygenation, H2O2, and Lipopolysaccharide (LPS), meanwhile, RvD1 also remarkably protected endothelial cells from H2O2-induced mitochondrial damage as evident from the decreased MMP and increased mito-ROS, which were associated with the preservation of VE-cadherin Conclusion RvD1 protects the heart against diabetic IR-induced injuries by attenuating endothelial permeability and mitochondrial damage. Our study also provide insight into a novel underlying mechanism and a new strategy for treating diabetic IR.