title: Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling.
abstract: 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.
authors.affiliation: Departments of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamaguchi
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirotani
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kashiwase
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
authors.forename: Shungo
authors.initials: S
authors.lastname: Hikoso
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takeda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Michio
authors.initials: M
authors.lastname: Asahi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Taniike
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Ikuko
authors.initials: I
authors.lastname: Tsujimoto
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hongo
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kusakari
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kurihara
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nishida
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
mesh_terms: 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
chemical_list: D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482859:Map3k5 protein, mouse