Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling.
Left ventricular remodeling that occurs after myocardial infarction (MI) and pressure overload is generally accepted as a determinant of the clinical course of heart failure. The molecular mechanism of this process, however, remains to be elucidated. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in stress-induced apoptosis. We used ASK1 knockout mice (ASK-/-) to test the hypothesis that ASK1 is involved in development of left ventricular remodeling. ASK-/- hearts showed no morphological or histological defects. Echocardiography and cardiac catheterization revealed normal global structure and function. Left ventricular structural and functional remodeling were determined 4 weeks after coronary artery ligation or thoracic transverse aortic constriction (TAC). ASK-/- had significantly smaller increases in left ventricular end-diastolic and end-systolic ventricular dimensions and smaller decreases in fractional shortening in both experimental models compared with WT mice. The number of terminal deoxynucleotidyl transferase biotin-dUDP nick end-labeling-positive myocytes after MI or TAC was decreased in ASK-/- compared with that in WT mice. Overexpression of a constitutively active mutant of ASK1 induced apoptosis in isolated rat neonatal cardiomyocytes, whereas neonatal ASK-/- cardiomyocytes were resistant to H2O2-induced apoptosis. An in vitro kinase assay showed increased ASK1 activity in heart after MI or TAC in WT mice. Thus, ASK1 plays an important role in regulating left ventricular remodeling by promoting apoptosis.
Yamaguchi
Osamu
O
Departments of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
Higuchi
Yoshiharu
Y
Hirotani
Shinichi
S
Kashiwase
Kazunori
K
Nakayama
Hiroyuki
H
Hikoso
Shungo
S
Takeda
Toshihiro
T
Watanabe
Tetsuya
T
Asahi
Michio
M
Taniike
Masayuki
M
Matsumura
Yasushi
Y
Tsujimoto
Ikuko
I
Hongo
Kenichi
K
Kusakari
Yoichiro
Y
Kurihara
Satoshi
S
Nishida
Kazuhiko
K
Ichijo
Hidenori
H
Hori
Masatsugu
M
Otsu
Kinya
K
D000818:Animals; D017209:Apoptosis; D001794:Blood Pressure; D001835:Body Weight; D002478:Cells, Cultured; D004452:Echocardiography; D017353:Gene Deletion; D006333:Heart Failure / Q000235:genetics; D006334:Heart Function Tests; D006339:Heart Rate; D006352:Heart Ventricles / Q000473:pathology* / Q000503:physiopathology; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D016277:Ventricular Function, Left
D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482859:Map3k5 protein, mouse