Overexpression of calmodulin induces cardiac hypertrophy by a calcineurin-dependent pathway.
The possible role of calcineurin in cardiac hypertrophy induced by calmodulin (CaM) overexpression in the heart was investigated. CaM transgenic (CaM-TG) mice developed marked cardiac hypertrophy and exhibited up-regulation of atrial natriuretic factor (ANF) and beta-myosin heavy chain gene expression in the heart during the first 2 weeks after birth. The activity of calcineurin in the heart was also significantly increased in CaM-TG mice compared with wild-type littermates. Treatment of CaM-TG mice with the calcineurin inhibitor FK506 (1mg/kg per day) prevented the increase in the heart-to-body weight ratio as well as that in cardiomyocyte width. FK506 also inhibited the induction of fetal-type cardiac gene expression in CaM-TG mice. Overexpression of CaM in cultured rat cardiomyocytes activated the ANF gene promoter in a manner sensitive to FK506. Activation of a calcineurin-dependent pathway thus contributes to the development of cardiac hypertrophy induced by CaM overexpression in the heart.
Obata
Koji
K
Department of Cardiovascular Genome Science, Nagoya University School of Medicine, Nagoya, Japan.
Nagata
Kohzo
K
Iwase
Mitsunori
M
Odashima
Mari
M
Nagasaka
Tetsuro
T
Izawa
Hideo
H
Murohara
Toyoaki
T
Yamada
Yoshiji
Y
Yokota
Mitsuhiro
M
D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism*; D002478:Cells, Cultured; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism*; D015398:Signal Transduction; D014018:Tissue Distribution; D015854:Up-Regulation
D002147:Calmodulin; D019703:Calcineurin