Inhibition of TGFβ‐activated protein kinase 1 ameliorates myocardial ischaemia/reperfusion injury via endoplasmic reticulum stress suppression

• Published in: Journal of cellular and molecular medicine Vol. 24; no. 12; pp. 6846 - 6859
• Main Authors: Zeng, Jingjing, Jin, Qike, Ruan, Yongxue, Sun, Changzheng, Xu, Guangyu, Chu, Maoping, Ji, Kangting, Wu, Lianpin, Li, Lei
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.06.2020; John Wiley and Sons Inc
• Subjects: Animals; Animals, Newborn; Apoptosis; Cardiomyocytes; Cardiovascular disease; Cell death; Coronary vessels; Down-Regulation; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Endothelium; Enzyme Activation; Enzymes; Free radicals; Gene Silencing; Glucose; Heart; Hypoxia; Ischemia; Kinases; Laboratory animals; Male; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - metabolism; Mice, Inbred C57BL; Myocardial infarction; myocardial ischaemia/reperfusion; Myocardial Reperfusion Injury - enzymology; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - physiopathology; Myocytes, Cardiac - metabolism; Original; Oxidative Stress; Protein kinase; Proteins; Reactive Oxygen Species - metabolism; Reperfusion; ROS; siRNA; TAK1; TAK1 protein; Transforming growth factor-b; St Louis Missouri; United States > US; China; TAK1; endoplasmic reticulum stress; ROS; myocardial ischaemia/reperfusion
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.15340

Transforming growth factor β‐activated protein kinase 1 (TAK1) involves in various biological responses and is a key regulator of cell death. However, the role of TAK1 on acute myocardial ischaemia/reperfusion (MI/R) injury is unknown. We observed that TAK1 activation increased significantly after MI/R and hypoxia/reoxygenation (H/R), and we hypothesized that TAK1 has an important role in MI/R injury. Mice (TAK1 inhibiting by 5Z‐7‐oxozeaenol or silencing by AAV9 vector) were exposed to MI/R injury. Primary cardiomyocytes (TAK1 silencing by siRNA; and overexpressing TAK1 by adenovirus vector) were used to induce H/R injury model in vitro. Inhibition of TAK1 significantly decreased MI/R‐induced myocardial infarction area, reduced cell death and improved cardiac function. Mechanistically, TAK1 silencing suppressed MI/R‐induced myocardial oxidative stress and attenuated endoplasmic reticulum (ER) stress both in vitro and in vivo. In addition, the inhibition of ROS by NAC partially reversed the damage of TAK1 in vitro. Our study presents the first direct evidence that inhibition of TAK1 mitigated MI/R injury, and TAK1 mediated ROS/ER stress/apoptosis signal pathway is important for the pathogenesis of MI/R injury.