Cyclic GMP Kinase and RhoA Ser188 Phosphorylation Integrate Pro- and Antifibrotic Signals in Blood Vessels
Cyclic GMP Kinase and RhoA Ser188 Phosphorylation Integrate Pro- and Antifibrotic Signals in Blood Vessels
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DOI：
10.1128/mcb.00225-09
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发表时间：
2009-09
影响因子：
5.3
通讯作者：
N. Sawada;H. Itoh;K. Miyashita;Hirokazu Tsujimoto;Masakatsu Sone;K. Yamahara;Z. Arany;F. Hofmann;K. Nakao
中科院分区：
文献类型：
--
作者：
N. Sawada;H. Itoh;K. Miyashita;Hirokazu Tsujimoto;Masakatsu Sone;K. Yamahara;Z. Arany;F. Hofmann;K. Nakao
摘要血管纤维化是高血压和动脉粥样硬化的主要并发症，但在很大程度上是无法治疗的。利钠肽(NPs)抑制血管平滑肌细胞(VSMCs)的纤维化激活，但其细胞内机制尚不清楚。在这里，我们表明，通过磷酸化抑制RhoA在Ser188，NP效应分子环GMP(CGMP)依赖的蛋白激酶I(CGK I)靶点，是充分发挥抗纤维化潜力的关键。CGK I+/−小鼠血管中P-RhoA水平降低，同时RhoA/ROCK信号增强。重要的是，CGK I的不足导致ROCK的动态募集进入纤维化程序，从而引起夸大的血管肥大和纤维化。与野生型RhoA相比，转基因表达CGK I-非磷酸化RhoAA188的VSMCs更显著地增强了ROCK活性、血管肥大和纤维化，这与RhoAA188逃避CGK I的内在抑制的观点一致。此外，表达RhoAA188的VSMCs对NPs的抗纤维化作用变得不耐受。我们的结果证实CGK I介导的RhoA Ser188磷酸化是促纤维化和抗纤维化信号的汇聚节点，并可能解释cGMP信号的减弱(通常与血管功能障碍相关)如何使个体易于发生血管纤维化。
ABSTRACT Vascular fibrosis is a major complication of hypertension and atherosclerosis, yet it is largely untreatable. Natriuretic peptides (NPs) repress fibrogenic activation of vascular smooth muscle cells (VSMCs), but the intracellular mechanism mediating this effect remains undetermined. Here we show that inhibition of RhoA through phosphorylation at Ser188, the site targeted by the NP effector cyclic GMP (cGMP)-dependent protein kinase I (cGK I), is critical to fully exert antifibrotic potential. cGK I+/− mouse blood vessels exhibited an attenuated P-RhoA level and concurrently increased RhoA/ROCK signaling. Importantly, cGK I insufficiency caused dynamic recruitment of ROCK into the fibrogenic programs, thereby eliciting exaggerated vascular hypertrophy and fibrosis. Transgenic expression of cGK I-unphosphorylatable RhoAA188 in VSMCs augmented ROCK activity, vascular hypertrophy, and fibrosis more prominently than did that of wild-type RhoA, consistent with the notion that RhoAA188 escapes the intrinsic inhibition by cGK I. Additionally, VSMCs expressing RhoAA188 became refractory to the antifibrotic effects of NPs. Our results identify cGK I-mediated Ser188 phosphorylation of RhoA as a converging node for pro- and antifibrotic signals and may explain how diminished cGMP signaling, commonly associated with vascular malfunction, predisposes individuals to vascular fibrosis.