Open AccessTargeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling
Author(s) -
Osamu Yamaguchi,
Yoshiharu Higuchi,
Shinichi Hirotani,
Kazunori Kashiwase,
Hiroyuki Nakayama,
Shungo Hikoso,
Toshihiro Takeda,
Tetsuya Watanabe,
Michio Asahi,
Masayuki Tanaka,
Yasushi Matsumura,
Ikuko Tsujimoto,
Kazuhiro Hongo,
Yoichiro Kusakari,
Satoshi Kurihara,
Keiya Nishida,
Hidenori Ichijo,
Masatsugu Hori,
Kinya Otsu
Publication year - 2003
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2136717100
Subject(s) - ventricular remodeling , ask1 , apoptosis , pressure overload , kinase , medicine , tunel assay , heart failure , myocardial infarction , biology , endocrinology , cardiology , protein kinase a , microbiology and biotechnology , cyclin dependent kinase 2 , biochemistry , cardiac hypertrophy
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.