title: p38alpha mitogen-activated protein kinase plays a critical role in cardiomyocyte survival but not in cardiac hypertrophic growth in response to pressure overload.
abstract: The molecular mechanism for the transition from cardiac hypertrophy, an adaptive response to biomechanical stress, to heart failure is poorly understood. The mitogen-activated protein kinase p38alpha is a key component of stress response pathways in various types of cells. In this study, we attempted to explore the in vivo physiological functions of p38alpha in hearts. First, we generated mice with floxed p38alpha alleles and crossbred them with mice expressing the Cre recombinase under the control of the alpha-myosin heavy-chain promoter to obtain cardiac-specific p38alpha knockout mice. These cardiac-specific p38alpha knockout mice were born normally, developed to adulthood, were fertile, exhibited a normal life span, and displayed normal global cardiac structure and function. In response to pressure overload to the left ventricle, they developed significant levels of cardiac hypertrophy, as seen in controls, but also developed cardiac dysfunction and heart dilatation. This abnormal response to pressure overload was accompanied by massive cardiac fibrosis and the appearance of apoptotic cardiomyocytes. These results demonstrate that p38alpha plays a critical role in the cardiomyocyte survival pathway in response to pressure overload, while cardiac hypertrophic growth is unaffected despite its dramatic down-regulation.
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nishida
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamaguchi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirotani
authors.forename: Shungo
authors.initials: S
authors.lastname: Hikoso
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takeda
authors.forename: Soh
authors.initials: S
authors.lastname: Osuka
authors.forename: Takashi
authors.initials: T
authors.lastname: Morita
authors.forename: Gen
authors.initials: G
authors.lastname: Kondoh
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uno
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kashiwase
authors.forename: Masayuki
authors.initials: M
authors.lastname: Taniike
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nakai
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Miyazaki
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Sudo
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: Kenneth R
authors.initials: KR
authors.lastname: Chien
authors.forename: Junji
authors.initials: J
authors.lastname: Takeda
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001794:Blood Pressure / Q000502:physiology*; D002470:Cell Survival; D015536:Down-Regulation; D005355:Fibrosis; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*
chemical_list: D048308:Mitogen-Activated Protein Kinase 14