Di Zhu1, Xiaotian Zhang2, Fenglin Wang1, Qiao Ye3, Caizhe Yang4, Demin Liu5. 1. Department of Endocrinology, Air Force Medical Center, Air Force Medical University, 30 Fucheng Road, Beijing 100142, China. 2. Hospital of Troop 75600, 3002 Fuqiang Road, Shenzhen 518048, China. 3. Clinical Medicine Laboratory, Air Force Medical Center, Air Force Medical University, 30 Fucheng Road, Beijing 100142, China. 4. Department of Endocrinology, Air Force Medical Center, Air Force Medical University, 30 Fucheng Road, Beijing 100142, China. Electronic address: yangcaizhe2008@163.com. 5. Department of Cardiology, Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang 050010, China. Electronic address: liudemincardiol@163.com.
Abstract
AIMS: 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.
AIMS: 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.
Authors: Foad Alzoughool; Mohammad Borhan Al-Zghoul; Bayan Y Ghanim; Michael Gollob; Nasir Idkaidek; Nidal A Qinna Journal: Pharmaceuticals (Basel) Date: 2022-07-14