Ischemic preconditioning or p38 MAP kinase inhibition attenuates myocardial TNF alpha production and mitochondria damage in brief myocardial ischemia.
Coronary artery occlusion increased the TNF alpha level in the membrane fraction of the rat heart, almost maximally at 30 min. TNF alpha immunofluorescence labeled streak-like reticular structures inside of the cardiomyocyte but not vascular or interstitial cells in myocardial ischemia. Immuno-electron microscopy confirmed the localization of TNF alpha between myofibrils, mitochondria, or other membrane structures in the ischemic cardiomyocyte. Ischemic preconditioning (IP) is the protection of myocardium conferred by cycles of brief ischemia-reperfusion. The increases in TNF alpha production, as well as phosphorylation of p38 MAP kinase and S6 kinase after ischemia were inhibited by IP or p38 MAP kinase inhibitors (SB203580, FR167653). TNF alpha production appeared to be regulated possibly at the post-transcriptional step by ribosomal S6 phosphorylation given that IP did not suppress TNF alpha mRNA up-regulation and was independent of NFkappaB activation. Electron microscopy (EM) showed mitochondria damage in ischemic cardiomyocyte, which was inhibited either by IP or SB203580. This is the first demonstration of the TNF alpha up-regulation in membrane structures of ischemic cardiomyocyte through p38 MAP kinase-mediated post-transcriptional mechanism, in association with mitochondrial damage.
Department of Forensic Medicine, Juntendo University School of Medicine, Hongo 2-1-1, Tokyo 113-8421, Japan.
Hiroko
H
Kimura
Kaori
K
Shintani-Ishida
Makoto
M
Nakajima
Shuang
S
Liu
Kazuko
K
Matsumoto
Ken-ichi
K
Yoshida
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000648:ultrastructure*; D017202:Myocardial Ischemia; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; C104334:FR 167653; D007093:Imidazoles; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580