Shimoyama M, Hayashi D, Zou Y, Takimoto E, Mizukami M, Monzen K, Kudoh S, Hiroi Y, Yazaki Y, Nagai R, Komuro I
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Circulation. 2000 Oct 17;102(16):1996-2004. doi: 10.1161/01.cir.102.16.1996.
It remains unclear how hemodynamic overload induces cardiac hypertrophy. Recently, activation of calcium-dependent phosphatase, calcineurin, has been elucidated to induce cardiac hypertrophy. In the present study, we examined the role of calcineurin in load-induced cardiac hypertrophy by using Dahl salt-sensitive (DS) rats, which develop both pressure and volume overload when fed a high salt diet.
In the DS rat heart, the activity of calcineurin was increased and cardiac hypertrophy was induced by high salt diet. Treatment of DS rats with the calcineurin inhibitor FK506 (0.1 or 0.01 mg/kg twice daily) from the age of 6 weeks to 12 weeks inhibited the activation of calcineurin in the heart in a dose-dependent manner and attenuated the development of load-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Additionally, treatment with 0.1 mg/kg twice daily but not with 0.01 mg/kg twice daily of FK506 from the age of 12 weeks to 16 weeks induced regression of cardiac hypertrophy in DS rats. Load-induced reprogramming of gene expression was also suppressed by the FK506 treatment.
These results suggest that calcineurin is involved in the development of cardiac hypertrophy in rats with salt-sensitive hypertension and that inhibition of calcineurin could induce regression of cardiac hypertrophy.
血流动力学过载如何诱发心肌肥大仍不清楚。最近，已阐明钙依赖性磷酸酶钙调神经磷酸酶的激活可诱发心肌肥大。在本研究中，我们使用 Dahl 盐敏感（DS）大鼠研究了钙调神经磷酸酶在负荷诱导的心肌肥大中的作用，这种大鼠在喂食高盐饮食时会出现压力和容量过载。
在 DS 大鼠心脏中，高盐饮食可增加钙调神经磷酸酶的活性并诱发心肌肥大。从 6 周龄至 12 周龄，用钙调神经磷酸酶抑制剂 FK506（0.1 或 0.01 mg/kg，每日两次）治疗 DS 大鼠，以剂量依赖的方式抑制心脏中钙调神经磷酸酶的激活，并减轻负荷诱导的心肌肥大和纤维化的发展，而血流动力学参数无变化。此外，从 12 周龄至 16 周龄，用 0.1 mg/kg 每日两次而非 0.01 mg/kg 每日两次的 FK506 治疗可诱导 DS 大鼠心肌肥大的消退。FK506 治疗还可抑制负荷诱导的基因表达重编程。
这些结果表明，钙调神经磷酸酶参与盐敏感性高血压大鼠心肌肥大的发展，抑制钙调神经磷酸酶可诱导心肌肥大的消退。
