Interleukin-17A Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Cardiomyocyte Apoptosis and Neutrophil Infiltration

• Published in: Journal of the American College of Cardiology Vol. 59; no. 4; pp. 420 - 429
• Main Authors: Liao, Yu-Hua, Xia, Ni, Zhou, Su-Feng, Tang, Ting-Ting, Yan, Xin-Xin, Lv, Bing-Jie, Nie, Shao-Fang, Wang, Jing, Iwakura, Yoichiro, Xiao, Hong, Yuan, Jing, Jevallee, Harish, Wei, Fen, Shi, Guo-Ping, Cheng, Xiang
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 24.01.2012; Elsevier; Elsevier Limited
• Subjects: Animals; Apoptosis; Biological and medical sciences; Cardiology; Cardiology. Vascular system; Cardiomyocytes; Cardiovascular; Cell Adhesion; Chemokines; Chemokines, CXC - metabolism; Coronary heart disease; Coronary vessels; E-Selectin - metabolism; Endothelial Cells - physiology; Endothelium; Gene Knockout Techniques; Heart; Heart attacks; Immune system; inflammation; Intercellular Adhesion Molecule-1 - metabolism; interleukin-17; Interleukin-17 - physiology; Ischemia; ischemia/reperfusion; Lymphocytes; Medical sciences; Mice; Mice, Inbred C57BL; Migration; Myocardial Reperfusion Injury - immunology; Myocardial Reperfusion Injury - metabolism; Myocarditis. Cardiomyopathies; Myocytes, Cardiac - physiology; Neutrophil Infiltration; Oxidative Stress; Proteins; Rodents; T-Lymphocyte Subsets - metabolism; γδT cell; EF; IL; ICAM; ELR; LV; mRNA; H2O2; FS; I/R; mAb; ischemia/reperfusion; LVEDP; interleukin-17; AAR; γδTCR; TUNEL; rIL; inflammation; MIP; KC; cTnT; LIX; γδT cell; EC; cardiac troponin T; ejection fraction; area at risk; γδT cell receptor-positive; messenger ribonucleic acid; left ventricle/ventricular; interleukin; terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling; lipopolysaccharide-induced CXC chemokine; endothelial cell; hydrogen peroxide; cytokine-induced neutrophil chemoattractant; recombinant interleukin; ischemia-reperfusion; left ventricular end-diastolic pressure; inter-cellular adhesion molecule; H 2O 2; macrophage inflammatory protein; glutamic acid–leucine-arginine; monoclonal antibody; fractional shortening; Heart; Interleukin; Granulocyte; Cardiovascular disease; Myocardial ischemia; Coronary heart disease; Myocardial disease; Myocyte; Vascular disease; Reperfusion; Infiltration; Circulatory system; Neutrophil; Cardiology; Apoptosis
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2011.10.863

This study tested whether interleukin (IL)-17A is involved in the pathogenesis of mouse myocardial ischemia/reperfusion (I/R) injury and investigated the mechanisms. Inflammatory processes play a major role in myocardial I/R injury. We recently identified IL-17A as an important cytokine in inflammatory cardiovascular diseases such as atherosclerosis and viral myocarditis. However, its role in myocardial I/R injury remains unknown. The involvement of IL-17A was assessed in functional assays in mouse myocardial I/R injury by neutralization/repletion or genetic deficiency of IL-17A, and its mechanism on cardiomyocyte apoptosis and neutrophil infiltration were further studied in vivo and in vitro. Interleukin-17A was elevated after murine left coronary artery ligation and reperfusion. Intracellular cytokine staining revealed that γδT lymphocytes but not CD4+ helper T cells were a major source of IL-17A. Anti–IL-17A monoclonal antibody treatment or IL-17A knockout markedly ameliorated I/R injury, as demonstrated by reduced infarct size, reduced cardiac troponin T levels, and improved cardiac function. This improvement was associated with a reduction in cardiomyocyte apoptosis and neutrophil infiltration. In contrast, repletion of exogenous IL-17A induced the opposite effect. In vitro study showed that IL-17A mediated cardiomyocyte apoptosis through regulating the Bax/Bcl-2 ratio, induced CXC chemokine-mediated neutrophil migration and promoted neutrophil-endothelial cell adherence through induction of endothelial cell E-selectin and inter-cellular adhesion molecule-1 expression. IL-17A mainly produced by γδT cells plays a pathogenic role in myocardial I/R injury by inducing cardiomyocyte apoptosis and neutrophil infiltration.