Zhang W, Kowal R C, Rusnak F, Sikkink R A, Olson E N, Victor R G
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Tex. 75235-8586, USA.
Circ Res. 1999 Apr 2;84(6):722-8. doi: 10.1161/01.res.84.6.722.
A rapidly emerging body of literature implicates a pivotal role for the Ca2+-calmodulin-dependent phosphatase calcineurin as a cellular target for a variety of Ca2+-dependent signaling pathways culminating in left ventricular hypertrophy (LVH). Most of the recent experimental support for this hypothesis is derived from in vitro studies or in vivo studies in transgenic mice expressing activated calcineurin or mutant sarcomeric proteins. The aim of the present study was to test whether calcineurin inhibitors, cyclosporin A (CsA) and FK 506, prevent pressure-overload LVH using 2 standard rat models: (1) the spontaneously hypertensive rat (SHR) and (2) aortic banding. The major new findings are 2-fold. First, in SHR, LVH (left ventricular weight to body weight ratio) was unaffected by a dose of CsA (5 mg. kg-1. d-1) that was sufficient to raise blood pressure and to inhibit calcineurin-mediated transcriptional activation in skeletal muscle. Second, in rats with aortic banding, LVH was unaffected by FK 506 (0.3 mg. kg-1. d-1) or even higher doses of CsA (10 and 20 mg. kg-1. d-1) that were sufficient to inhibit 90% of total calcineurin phosphatase activity in the hypertrophied myocardium. In the latter experiments, CsA blocked neither the elevated left ventricular end-diastolic pressures, a measure of diastolic function, nor the induction in atrial natriuretic peptide mRNA in the hypertrophic ventricles. Thus, in numerous experiments, systemic administration of potent calcineurin inhibitors did not prevent the development of LVH in 2 classic models of pressure-overload hypertrophy. These results demonstrate that pressure-overload hypertrophy can arise through calcineurin-independent pathways.
迅速涌现的大量文献表明，钙调神经磷酸酶这种依赖于钙离子 - 钙调蛋白的磷酸酶在多种依赖钙离子的信号通路中起关键作用，这些信号通路最终导致左心室肥厚（LVH）。最近对这一假说的大多数实验支持来自体外研究或在表达活化钙调神经磷酸酶或突变肌节蛋白的转基因小鼠中的体内研究。本研究的目的是使用两种标准大鼠模型来测试钙调神经磷酸酶抑制剂环孢素A（CsA）和FK 506是否能预防压力超负荷引起的左心室肥厚：（1）自发性高血压大鼠（SHR）和（2）主动脉缩窄。主要的新发现有两点。首先，在SHR中，左心室肥厚（左心室重量与体重之比）不受足以升高血压并抑制骨骼肌中钙调神经磷酸酶介导的转录激活的CsA剂量（5 mg·kg⁻¹·d⁻¹）的影响。其次，在主动脉缩窄的大鼠中，左心室肥厚不受FK 506（0.3 mg·kg⁻¹·d⁻¹）甚至更高剂量的CsA（10和20 mg·kg⁻¹·d⁻¹）的影响，这些剂量足以抑制肥厚心肌中90%的总钙调神经磷酸酶磷酸酶活性。在后面的实验中，CsA既没有阻止升高的左心室舒张末期压力（一种舒张功能的指标），也没有阻止肥厚心室中利钠肽mRNA的诱导。因此，在众多实验中，全身给予强效钙调神经磷酸酶抑制剂并不能预防两种经典的压力超负荷肥厚模型中左心室肥厚的发展。这些结果表明，压力超负荷肥厚可通过不依赖钙调神经磷酸酶的途径发生。
