Murat A, Pellieux C, Brunner H R, Pedrazzini T
Division of Hypertension, University of Lausanne Medical School, CH-1011 Lausanne, Switzerland.
J Biol Chem. 2000 Dec 29;275(52):40867-73. doi: 10.1074/jbc.M008071200.
Chronic stimulation of the renin-angiotensin system induces an elevation of blood pressure and the development of cardiac hypertrophy via the actions of its effector, angiotensin II. In cardiomyocytes, mitogen-activated protein kinases as well as protein kinase C isoforms have been shown to be important in the transduction of trophic signals. The Ca(2+)/calmodulin-dependent phosphatase calcineurin has also been suggested to play a role in cardiac growth. In the present report, we investigate possible cross-talks between calcineurin, protein kinase C, and mitogen-activated protein kinase pathways in controlling angiotensin II-induced hypertrophy. Angiotensin II-stimulated cardiomyocytes and mice with angiotensin II-dependent renovascular hypertension were treated with the calcineurin inhibitor cyclosporin A. Calcineurin, protein kinase C, and mitogen-activated protein kinase activations were determined. We show that cyclosporin A blocks angiotensin II-induced mitogen-activated protein kinase activation in cultured primary cardiomyocytes and in the heart of hypertensive mice. Cyclosporin A also inhibits specific protein kinase C isoforms. In vivo, cyclosporin A prevents the development of cardiac hypertrophy, and this effect appears to be independent of hemodynamic changes. These data suggest cross-talks between the calcineurin pathway, the protein kinase C, and the mitogen-activated protein kinase signaling cascades in transducing angiotensin II-mediated stimuli in cardiomyocytes and could provide the basis for an integrated model of cardiac hypertrophy.
肾素 - 血管紧张素系统的慢性刺激通过其效应物血管紧张素II的作用导致血压升高和心脏肥大的发展。在心肌细胞中，丝裂原活化蛋白激酶以及蛋白激酶C亚型已被证明在营养信号转导中起重要作用。钙调神经磷酸酶，一种依赖于Ca(2 +)/钙调蛋白的磷酸酶，也被认为在心脏生长中发挥作用。在本报告中，我们研究了钙调神经磷酸酶、蛋白激酶C和丝裂原活化蛋白激酶途径在控制血管紧张素II诱导的肥大过程中可能存在的相互作用。用钙调神经磷酸酶抑制剂环孢素A处理血管紧张素II刺激的心肌细胞和患有血管紧张素II依赖性肾血管性高血压的小鼠。测定钙调神经磷酸酶、蛋白激酶C和丝裂原活化蛋白激酶的激活情况。我们发现环孢素A可阻断培养的原代心肌细胞和高血压小鼠心脏中血管紧张素II诱导的丝裂原活化蛋白激酶激活。环孢素A还抑制特定的蛋白激酶C亚型。在体内，环孢素A可防止心脏肥大的发展，且这种作用似乎与血流动力学变化无关。这些数据表明在心肌细胞中，钙调神经磷酸酶途径、蛋白激酶C和丝裂原活化蛋白激酶信号级联在转导血管紧张素II介导的刺激过程中存在相互作用，这可能为心脏肥大的综合模型提供基础。
