p38alpha mitogen-activated protein kinase plays a critical role in cardiomyocyte survival but not in cardiac hypertrophic growth in response to pressure overload.
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.
Nishida
Kazuhiko
K
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Yamaguchi
Osamu
O
Hirotani
Shinichi
S
Hikoso
Shungo
S
Higuchi
Yoshiharu
Y
Watanabe
Tetsuya
T
Takeda
Toshihiro
T
Osuka
Soh
S
Morita
Takashi
T
Kondoh
Gen
G
Uno
Yoshihiro
Y
Kashiwase
Kazunori
K
Taniike
Masayuki
M
Nakai
Atsuko
A
Matsumura
Yasushi
Y
Miyazaki
Jun-ichi
J
Sudo
Tatsuhiko
T
Hongo
Kenichi
K
Kusakari
Yoichiro
Y
Kurihara
Satoshi
S
Chien
Kenneth R
KR
Takeda
Junji
J
Hori
Masatsugu
M
Otsu
Kinya
K
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*
D048308:Mitogen-Activated Protein Kinase 14