title: Apoptosis signal-regulating kinase 1/p38 signaling pathway negatively regulates physiological hypertrophy.
abstract: BACKGROUND
  Mechanical stress on the heart can lead to crucially different outcomes. Physiological stimuli such as exercise cause adaptive cardiac hypertrophy, characterized by a normal cardiac structure and normal or enhanced cardiac function. Pathological stimuli such as hypertension and aortic valvular stenosis cause maladaptive cardiac remodeling and ultimately heart failure. Apoptosis signal-regulating kinase 1 (ASK1) is known to be involved in pathological cardiac remodeling, but it has not been determined whether ASK1 pathways coordinate the signaling cascade leading to physiological type cardiac growth.
  
  
  RESULTS
  To evaluate the role of ASK1 in the physiological form of cardiac growth, mice lacking ASK1 (ASK1-/-) were exercised by swimming for 4 weeks. ASK1-/- mice showed exaggerated growth of the heart accompanied by typical characteristics of physiological hypertrophy. Their swimming-induced activation of Akt, a key molecule in the signaling cascade of physiological hypertrophy, increased more than that seen in wild-type controls. The activation of p38, a downstream kinase of ASK1, was suppressed selectively in the swimming-exercised ASK1-/- mice. Furthermore, the inhibition of ASK1 or p38 activity enhanced insulin-like growth factor 1-induced protein synthesis in rat neonatal ventricular cardiomyocytes, and the treatment with a specific inhibitor of p38 resulted in enhancement of Akt activation and suppression of protein phosphatase 2A activation. The cardiac-specific p38alpha-deficient mice developed an exacerbated form of cardiac hypertrophy in response to swimming exercise.
  
  
  CONCLUSIONS
  These results indicate that the ASK1/p38 signaling pathway negatively regulates physiological hypertrophy.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Taniike
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamaguchi
authors.forename: Ikuko
authors.initials: I
authors.lastname: Tsujimoto
authors.forename: Shungo
authors.initials: S
authors.lastname: Hikoso
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takeda
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nakai
authors.forename: Shigemiki
authors.initials: S
authors.lastname: Omiya
authors.forename: Isamu
authors.initials: I
authors.lastname: Mizote
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nakano
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsumura
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; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism; D006984:Hypertrophy / Q000209:etiology; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010805:Physical Conditioning, Animal / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse