Takeda Yoshiyu, Yoneda Takashi, Demura Masashi, Usukura Mikiya, Mabuchi Hiroshi
Second Department of Internal Medicine, Kanazawa University, Kanazawa, Japan.
Circulation. 2002 Feb 12;105(6):677-9. doi: 10.1161/hc0602.104675.
It remains unclear how mineralocorticoids induce cardiac hypertrophy and fibrosis. Recently, activation of the calcium-dependent phosphatase, calcineurin, has been shown to induce cardiac hypertrophy. In the present study, we examine the role of calcineurin in mineralocorticoid-induced cardiac hypertrophy and fibrosis.
Uninephrectomized Wistar-Kyoto rats were placed on a 1.0% NaCl diet and treated with aldosterone (0.75 microg x h(-1)) for 6 weeks with or without the calcineurin inhibitors, FK506 (0.5 mg x kg(-1) x d(-1)) or cyclosporine A (10 mg x kg(-1) x d(-1)). The effect of the angiotensin II type 1 receptor antagonist, losartan (10 mg x kg(-1) x d(-1))on aldosterone-induced cardiac hypertrophy was also studied. Treatment with aldosterone increased the heart weight/body weight ratio, cardiomyocyte size, and collagen amount. The expression of mRNA of both type-III collagen and atrial natriuretic peptide in the heart were increased by aldosterone administration. Both calcineurin activity and its mRNA expression were also increased in aldosterone-induced hypertrophic heart. Treatment with losartan, FK506, or cyclosporine partially prevented aldosterone-induced cardiac hypertrophy and fibrosis.
These results suggest that calcineurin is involved in the development of cardiac hypertrophy and fibrosis induced by mineralocorticoid excess. Inhibition of calcineurin may therefore prevent cardiac hypertrophy and fibrosis in mineralocorticoid hypertension.
盐皮质激素如何诱导心脏肥大和纤维化仍不清楚。最近，已表明钙依赖性磷酸酶钙调神经磷酸酶的激活可诱导心脏肥大。在本研究中，我们研究了钙调神经磷酸酶在盐皮质激素诱导的心脏肥大和纤维化中的作用。
将单侧肾切除的Wistar-Kyoto大鼠置于1.0%氯化钠饮食中，并给予醛固酮（0.75微克×小时-1）处理6周，同时给予或不给予钙调神经磷酸酶抑制剂FK506（0.5毫克×千克-1×天-1）或环孢素A（10毫克×千克-1×天-1）。还研究了血管紧张素II 1型受体拮抗剂氯沙坦（10毫克×千克-1×天-1）对醛固酮诱导的心脏肥大的影响。醛固酮处理增加了心脏重量/体重比、心肌细胞大小和胶原蛋白含量。醛固酮给药使心脏中III型胶原蛋白和心房利钠肽的mRNA表达均增加。在醛固酮诱导的肥大心脏中，钙调神经磷酸酶活性及其mRNA表达也增加。氯沙坦、FK506或环孢素处理部分预防了醛固酮诱导的心脏肥大和纤维化。
这些结果表明钙调神经磷酸酶参与了盐皮质激素过多诱导的心脏肥大和纤维化的发展。因此，抑制钙调神经磷酸酶可能预防盐皮质激素性高血压中的心脏肥大和纤维化。
