Apoptosis signal-regulating kinase 1 is involved not only in apoptosis but also in non-apoptotic cardiomyocyte death.
The molecular basis of myocardial cell death in the ischemia-reperfused heart still remains to be clarified. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in stress-induced apoptosis. We studied ASK1(-/-) mice to examine the role of ASK1 in ischemia-reperfusion injury. In the wild-type heart, ischemia-reperfusion resulted in necrotic injury, whereas infarct size was drastically reduced in the ASK1(-/-) heart. The necrotic injury was not accompanied with any evidence of apoptosis such as an increase in TUNEL-positive cells, DNA fragmentation or the activation of caspase-3. ASK1(-/-) cardiomyocytes were more resistant to H(2)O(2)- or Ca(2+)-induced apoptotic and non-apoptotic cell death compared with wild-type cells. These data suggest that ASK1 is involved in necrosis as well as apoptosis and that ASK1-dependent necrosis is likely to contribute to myocardial cell death in the ischemia-reperfused heart.
Watanabe
Tetsuya
T
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
Otsu
Kinya
K
Takeda
Toshihiro
T
Yamaguchi
Osamu
O
Hikoso
Shungo
S
Kashiwase
Kazunori
K
Higuchi
Yoshiharu
Y
Taniike
Masayuki
M
Nakai
Atsuko
A
Matsumura
Yasushi
Y
Nishida
Kazuhiko
K
Ichijo
Hidenori
H
Hori
Masatsugu
M
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D048848:MAP Kinase Kinase Kinase 5 / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology*; D009336:Necrosis; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology*
D048848:MAP Kinase Kinase Kinase 5