Pericardial fluid from patients with ischemic heart disease induces myocardial cell apoptotis via an oxidant stress-sensitive p38 mitogen-activated protein kinase pathway.
Factors produced by the heart are accumulated at high concentrations in pericardial fluid. We recently reported that pericardial fluid from patients with ischemic heart disease induces apoptosis in an F2 cell line. To characterize factors in pericardial fluid from patients with ischemic heart disease, we investigated signaling pathways by which this pericardial fluid induces apoptosis in cardiac myocytes. Pericardial fluid from patients with ischemic heart disease markedly increased the percentage of TUNEL-positive myocytes compared with fetal bovine serum. Apoptosis was also confirmed by ladder formation and morphologic features. Apoptosis mediated by this pericardial fluid occurs as readily in cardiac myocytes prepared from neonatal mice nullizygous for p53 as in wild-type littermates. This indicates that p53 is not required for this process. We have found that pericardial fluid from ischemic heart disease elicits a robust increase in phosphorylation of p38 mitogen-activated protein kinase. Specific inhibition of the p38 mitogen-activated protein kinase pathway with SB 203580 almost completely blocked apoptosis mediated by pericardial fluid from ischemic heart disease. Activation of p38 mitogen-activated protein kinase is caused by cellular stress, including oxidants. We have also found that anti-oxidant catalase inhibited pericardial fluid-induced activation of p38 mitogen-activated protein kinase and apoptosis. These findings demonstrate that myocardial cell apoptosis induced by pericardial fluid from patients with ischemic heart disease is mediated by an oxidant stress-sensitive p38 mitogen-activated protein kinase pathway. A possible application of SB 203580 to preserve cardiac function in patients with ischemic heart disease should be discussed.
Iwakura
A
A
Department of Cardiovascular Surgery, Kyoto University, 53 Kawahara-cho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Fujita
M
M
Hasegawa
K
K
Toyokuni
S
S
Sawamura
T
T
Nohara
R
R
Sasayama
S
S
Komeda
M
M
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology*; D016877:Oxidants; D018384:Oxidative Stress; D010490:Pericardial Effusion / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D016877:Oxidants; D016159:Tumor Suppressor Protein p53; D000080242:8-Hydroxy-2'-Deoxyguanosine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003849:Deoxyguanosine