Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes
Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes
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DOI：
10.1073/pnas.162100799
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发表时间：
2002-08-20
影响因子：
11.1
通讯作者：
Wollert, KC
中科院分区：
文献类型：
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作者：
Fiedler, B;Lohmann, SM;Wollert, KC
最近的研究集中在确定抑制心脏肥大的信号通路，心脏肥大是心血管发病率和死亡率的主要危险因素。在这种情况下，一氧化氮（NO），通过cGMP和cGMP依赖性蛋白激酶I型（PKG 1）的信号转导，已被认为是心肌细胞（CM）肥大的负调节剂。然而，人们对其潜在机制知之甚少。在这里，我们表明，PKG I抑制CM肥大靶向钙调神经磷酸酶-NFAT信号通路。钙调神经磷酸酶是一种Ca 2+依赖性磷酸酶，部分通过激活NFAT转录因子促进肥大，NFAT转录因子诱导肥大基因（包括脑钠肽（BNP））的表达。在CM中通过NO/cGMP激活PKG I抑制了NFAT转录活性、BNP诱导和对α（1）-肾上腺素受体刺激的细胞增大，但不对Ca 2+非依赖性、组成性活性钙调磷酸酶突变体的腺病毒表达作出反应，因此证明了NO-cGMP-PKG I抑制钙调磷酸酶-NFAT信号传导上游的钙调磷酸酶。PKG I抑制单个L型Ca 2+通道开放概率、[Ca 2 +]、瞬时振幅，最重要的是，抑制L型Ca 2+通道电流诱导的NFAT激活，表明PKG I靶向钙调磷酸酶上游的Ca 2+依赖性步骤。PKG I的腺病毒表达增强了钙调神经磷酸酶上游的NO/cGMP抑制作用，证实PKG I介导了钙调神经磷酸酶-NFAT信号传导的NO/cGMP抑制。在过表达PKG 1的CM中，NO/cGMP还抑制BNP诱导和细胞增大，但不抑制组成性活性钙调磷酸酶引起的NFAT激活，这与钙调磷酸酶下游PKG I的额外、NFAT非依赖性抑制作用一致。PKG I对钙调神经磷酸酶-NFAT信号传导的抑制为理解NO如何抑制心肌细胞肥大提供了框架。
Recent investigation has focused on identifying signaling pathways that inhibit cardiac hypertrophy, a major risk factor for cardiovascular morbidity and mortality. In this context, nitric oxide (NO), signaling via cGMP and cGMP-dependent protein kinase type I (PKG 1), has been recognized as a negative regulator of cardiac myocyte (CM) hypertrophy. However, the underlying mechanisms are poorly understood. Here, we show that PKG I inhibits CM hypertrophy by targeting the calcineurin-NFAT signaling pathway. Calcineurin, a Ca2+-dependent phosphatase, promotes hypertrophy in part by activating NFAT transcription factors which induce expression of hypertrophic genes, including brain natriuretic peptide (BNP). Activation of PKG I by NO/cGMP in CM suppressed NFAT transcriptional activity, BNP induction, and cell enlargement in response to alpha(1)-adrenoreceptor stimulation but not in response to adenoviral expression of a Ca2+-independent, constitutively active calcineurin mutant, thus demonstrating NO-cGMP-PKG I inhibition of calcineurin-NFAT signaling upstream of calcineurin. PKG I suppressed single L-type Ca2+-channel open probability, [Ca2+], transient amplitude, and, most importantly, L-type Ca2+-channel current-induced NFAT activation, indicating that PKG I targets Ca2+-dependent steps upstream of calcineurin. Adenoviral expression of PKG I enhanced NO/cGMP inhibitory effects upstream of calcineurin, confirming that PKG I mediates NO/cGMP inhibition of calcineurin-NFAT signaling. In CM overexpressing PKG 1, NO/cGMP also suppressed BNP induction and cell enlargement but not NFAT activation elicited by constitutively active calcineurin, which is consistent with additional, NFAT-independent inhibitory effect(s) of PKG I downstream of calcineurin. Inhibition of calcineurin-NFAT signaling by PKG I provides a framework for understanding how NO inhibits cardiac myocyte hypertrophy.