Obata Koji, Nagata Kohzo, Iwase Mitsunori, Odashima Mari, Nagasaka Tetsuro, Izawa Hideo, Murohara Toyoaki, Yamada Yoshiji, Yokota Mitsuhiro
Department of Cardiovascular Genome Science, Nagoya University School of Medicine, Nagoya, Japan.
Biochem Biophys Res Commun. 2005 Dec 16;338(2):1299-305. doi: 10.1016/j.bbrc.2005.10.083. Epub 2005 Oct 24.
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.
研究了钙调神经磷酸酶在心脏中钙调蛋白（CaM）过表达诱导的心肌肥大中的可能作用。CaM转基因（CaM-TG）小鼠在出生后的前2周出现明显的心肌肥大，并表现出心脏中的心钠素（ANF）和β-肌球蛋白重链基因表达上调。与野生型同窝小鼠相比，CaM-TG小鼠心脏中钙调神经磷酸酶的活性也显著增加。用钙调神经磷酸酶抑制剂FK506（每天1mg/kg）治疗CaM-TG小鼠可防止心脏与体重比以及心肌细胞宽度的增加。FK506还抑制了CaM-TG小鼠中胎儿型心脏基因表达的诱导。在培养的大鼠心肌细胞中CaM的过表达以对FK506敏感的方式激活了ANF基因启动子。因此，钙调神经磷酸酶依赖性途径的激活有助于心脏中CaM过表达诱导的心肌肥大的发展。
