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

Abstract

Cardiac 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).Methods: T2DM 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.Results: Irisin 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. Conclusion:Irisin could rescue cardiac microvessels against oxidative stress and apoptosis in diabetes via ERK1/2/Nrf2/HO-1 pathway.

Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53

“…To further verify the role of ferroptosis on irisin-mediated protection of DCM in T1DM in mice, we administered the ferroptosis inducer erastin (40 mg/kg body weight/day, for 3 consecutive days) to STZ-induced diabetic mice [ 35 ]. The protective effects of irisin on the heart of STZ-induced diabetic mice included improvement in cardiac function, mitigation of pathological structure disorder and fibrosis, and restoration of mitochondrial structure in cardiomyocytes.…”

The Role of Interventional Irisin on Heart Molecular Physiology

“…A study by Khorasani et al showed that irisin levels were relatively lower in diabetic patients with cardiovascular complications in comparison to uncomplicated diabetic patients [ 43 ]. On the contrary, other studies concluded that increased irisin levels mediate cardioprotection in diabetic subjects and inhibit myocardial apoptosis, implicating irisin as a potential therapeutic intervention during diabetic cardiomyopathy [ 44 , 45 , 46 ].…”

The emerging roles of irisin in vascular calcification

“…In addition, oxidative stress facilitates the occurrence and development of vascular calcification through NADPH oxidase and its downstream ERK signaling pathway (93). By activating Nrf2/HO-1 signaling pathway, irisin could increase the expression of key antioxidant enzymes, such as catalase-9, superoxide dismutase, and glutathione peroxidase, and inhibit the production of hydrogen peroxide, so as to protect vascular endothelial cells from cellular oxidative damage (94). Irisin has been clearly confirmed to have an antioxidant function, and the antioxidant mechanism of irisin is associated with important cellular processes by reducing ROS and its complications, including regulation of mitochondrial fission and fusion, inhibition of inflammasome activation, improvement of autophagy, inhibition of endoplasmic reticulum stress and ferroptosis, and reversal of cell death (95).…”