Disruption of a single copy of the p38alpha MAP kinase gene leads to cardioprotection against ischemia-reperfusion.
The p38 mitogen-activated protein kinase (p38) is activated in the heart during ischemia-reperfusion. However, it is not clear whether the activation of p38 is the protective response or the kinase mediates the cellular damage by ischemia-reperfusion. We examined the role of p38alpha in ischemia-reperfusion injury by studying p38alpha(+/-) mice. The p38alpha protein level in the p38alpha(+/-) heart was 50+/-8.7% compared with that in the p38alpha(+/+) heart. Upon reperfusion following ischemia for 25min, p38alpha activity was transiently increased. The maximum level of p38 activity in p38alpha(+/-) was 60+/-10.5% compared with that in p38alpha(+/+). In the p38alpha(+/+) heart, 25min ischemia and 2h reperfusion resulted in necrotic injury (37.1+/-2.7% of the area at risk), whereas infarct size was drastically reduced to 7.2+/-0.7% in the p38alpha(+/-) heart. These suggested that p38alpha plays a pivotal role in the signal transduction pathway mediating myocardial cell death caused by ischemia-reperfusion.
Otsu
Kinya
K
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. kotsu@medone.med.osaka-u.ac.jp
Yamashita
Nobushige
N
Nishida
Kazuhiko
K
Hirotani
Shinichi
S
Yamaguchi
Osamu
O
Watanabe
Tetsuya
T
Hikoso
Shungo
S
Higuchi
Yoshiharu
Y
Matsumura
Yasushi
Y
Maruyama
Masumi
M
Sudo
Tatsuhiko
T
Osada
Hiroyuki
H
Hori
Masatsugu
M
D000818:Animals; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017202:Myocardial Ischemia / Q000201:enzymology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control*; D048051:p38 Mitogen-Activated Protein Kinases
D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases