Glycogen synthase kinase 3 inhibition protects the heart from acute ischemia-reperfusion injury via inhibition of inflammation and apoptosis.
Glycogen synthase kinase (GSK)-3beta inhibitors play an anti-inflammatory role in several inflammatory diseases. Recent studies have demonstrated that GSK-3beta inhibitors protect against myocardial ischemia-reperfusion injury. However, the precise mechanisms remain unclear. We aimed to investigate the roles of inflammation and apoptosis induced by ischemia-reperfusion in the cardioprotection by GSK-3beta inhibitor 4-benzyl-2-methyl-1, 2, 4-thiadiazolidine-3, 5-dione (TDZD-8). Anaesthetized Sprague-Dawley rats underwent an open-chest procedure involving 30 min of myocardial ischemia and 6 h of reperfusion with or without TDZD-8 given at reperfusion. TDZD-8 reduced myocardial infarct size by nearly 43% (P < 0.05 vs. myocardial ischemia-reperfusion) and attenuated myeloperoxidase activity (21.80 +/- 1.07 U/100 mg tissue. vs. myocardial ischemia-reperfusion group, P < 0.05). Administration of TDZD-8 significantly suppressed nuclear factor kappa B (NF-kappaB) and p38 MAPK activation (P < 0.05 vs. myocardial ischemia-reperfusion) and the concentrations of the myocardial-derived cytokines tumor necrosis factor-alpha (TNF-alpha, 107.40 +/- 7.34 pg/mg protein vs. myocardial ischemia-reperfusion group, P < 0.05) and interleukin-6 (IL-6, 29.28 +/- 6.3 pg/mg protein vs. myocardial ischemia-reperfusion group, P < 0.05). Treatment with TDZD-8 also inhibited myocardial cell apoptosis compared with the myocardial ischemia-reperfusion group (12 +/- 1% vs. 22 +/- 2%, P < 0.05). Therefore, blocking this protein kinase activity may be a novel approach to the treatment of this condition, which is characterized by inflammation and apoptosis.
Gao
Hao-Kao
HK
Department of Cardiology, Xi Jing Hospital, Fourth Military Medical University; Xi'an, China.
Yin
Zhong
Z
Zhou
Ning
N
Feng
Xu-Yang
XY
Gao
Feng
F
Wang
Hai-Chang
HC
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013830:Thiadiazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D016328:NF-kappa B; D013830:Thiadiazoles; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3