Calcineurin expression, activation, and function in cardiac pressure-overload hypertrophy
Calcineurin expression, activation, and function in cardiac pressure-overload hypertrophy
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DOI：
10.1161/01.cir.101.20.2431
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发表时间：
2000-05-23
期刊：
影响因子：
37.8
通讯作者：
Molkentin, JD
中科院分区：
文献类型：
--
作者：
Lim, HW;De Windt, LJ;Molkentin, JD
背景：血管高血压导致心脏负荷增加与左心室肥厚相关，是进展性心脏病的主要预测指标。响应心脏负荷增加的分子信号通路尚不清楚。肥厚反应的一个潜在调节因子是钙敏感磷酸酶钙调磷酸酶。方法和结果-我们发现，大鼠腹主动脉束带引起的压力超负荷肥厚，心脏钙调磷酸酶酶活性增加了3.2倍。Western blot分析进一步表明，钙调神经磷酸酶A（催化亚基）蛋白含量和与钙调蛋白的关联在压力过载肥厚的反应中增加。钙调磷酸酶蛋白含量的增加可以通过钙调磷酸酶抑制剂环孢素A （CsA）来预防，在14天的治疗方案中，CsA以剂量依赖的方式减轻了负荷引起的心脏肥厚。CsA给药14天后也能部分逆转主动脉束带大鼠的压力过载肥厚。CsA还能减轻压力过载肥厚的组织学和分子指标。结论-这些数据表明钙调磷酸酶是负荷性肥大的重要上游调节因子。
Background-Vascular hypertension resulting in increased cardiac load is associated with left ventricular hypertrophy and is a leading predicator for progressive heart disease. The molecular signaling pathways that respond to increases in cardiac load are poorly understood. One potential regulator of the hypertrophic response is the calcium-sensitive phosphatase calcineurin.Methods and Results-We showed that calcineurin enzymatic activity is increased 3.2-fold in the heart in response to pressure-overload hypertrophy induced by abdominal aortic banding in the rat. Western blot analysis further demonstrates that calcineurin A (catalytic subunit) protein content and association with calmodulin are increased in response to pressure-overload hypertrophy. This increase in calcineurin protein content was prevented by administration of the calcineurin inhibitor cyclosporine A (CsA), CsA administration attenuated load-induced cardiac hypertrophy in a dose-dependent manner over a 14-day treatment protocol. CsA administration also partially reversed pressure-overload hypertrophy in aortic-banded rats after 14 days. CsA also attenuated the histological and molecular indexes of pressure-overload hypertrophy.Conclusions-These data suggest that calcineurin is an important upstream regulator of load-induced hypertrophy.