Irisin rescues diabetic cardiac microvascular injury via ERK1/2/Nrf2/HO-1 mediated inhibition of oxidative stress

Abstract

AimsCardiac microvascular dysfunction is a common feature across cardiovascular complications in diabetes, while effective therapy remains elusive. This study was designed to evaluate the effect of irisin on cardiac microvascular injury in type 2 diabetes mellitus (T2DM). MethodsT2DM was induced in C57BL/6J mice. A cohort diabetic mice received a 12-week treatment of irisin. Cardiac function and microvessel density were evaluated. Whether irisin directly regulates cardiac microvascular endothelial cells (CMECs) function was determined in vitro. Discovery-drive approaches followed by cause-effect analysis were used to uncover the molecular mechanisms. ResultsIrisin improved cardiac function in diabetic mice, and increased microvessel density. In vitro study revealed that irisin promoted CMECs proliferation and reduced high glucose and high lipid (HGHL)-induced apoptosis. Mechanistically, irisin increased mRNA and protein levels of heme oxygenase 1 (HO-1), superoxide dismutase 1 and superoxide dismutase 2, among which HO-1 ranked top. Irisin stimulated the phosphorylation of extracellular regulated protein kinases (ERK) 1/2 and nuclear factor erythroid-derived 2—like 2 (Nrf2) nuclear translocation, while U0126 (the inhibitor of ERK1/2) inhibited irisin-induced Nrf2 nuclear translocation and HO-1 expression. Nrf2 siRNA inhibited irisin’s antioxidative effects. ConclusionIrisin could rescue cardiac microvessels against oxidative stress and apoptosis in diabetes via ERK1/2/Nrf2/HO-1 pathway.