Activation of RhoA and inhibition of myosin phosphatase as important components in hypertension in vascular smooth muscle
Activation of RhoA and inhibition of myosin phosphatase as important components in hypertension in vascular smooth muscle
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DOI：
10.1161/01.res.0000059987.90200.44
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发表时间：
2003-03-07
影响因子：
20.1
通讯作者：
Nakano, T
中科院分区：
文献类型：
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作者：
Seko, T;Ito, M;Nakano, T
研究人员提出了两种机制来解释肌球蛋白磷酸酶（MP）在血管肌Ca2+敏化过程中的抑制作用，即MYPT1 （MP的靶亚基）或CPI-17（一种抑制性磷酸化蛋白）的磷酸化。在培养的血管主动脉平滑肌细胞（VSMCs）中，血管紧张素II刺激激活RhoA，并通过8-溴- cgmp预处理阻断RhoA。血管紧张素II、内皮素-1或U-46619刺激的VSMCs显著增加了MYPT1 （Thr696位点）和CPI-17 （Thr38位点）的磷酸化水平。血管紧张素ii诱导的MYPT1磷酸化被8-溴- cgmp或Y-27632（一种rho激酶抑制剂）完全阻断，但不被GF109203X （PKC抑制剂）阻断。相比之下，CPI-17的磷酸化仅被GF109203X抑制。Y-27632可显著改善n -omega-硝基- l -精氨酸甲酯（L-NAME）治疗大鼠的高血压，且该高血压对单硝酸异山梨酯敏感。l - name处理大鼠主动脉中RhoA活性形式的水平明显升高。经l - name处理的大鼠主动脉中RhoA、RhoA激酶、MYPT1、CPI-17和肌球蛋白轻链激酶的表达与对照组无显著差异。在其他三种高血压大鼠模型（即卒中易发自发性高血压大鼠、肾性高血压大鼠和doca盐大鼠）中，RhoA被激活，而其他信号分子水平未发生变化。这些结果表明，与高血压的病因无关，下游信号传导的一个共同点和高血压的一个关键组成部分是RhoA的激活和随后的rho激酶的激活。
Two mechanisms are proposed to account for the inhibition of myosin phosphatase (MP) involved in Ca2+ sensitization of vascular muscle, ie, phosphorylation of either MYPT1, a target subunit of MP or CPI-17, an inhibitory phosphoprotein. In cultured vascular aorta smooth muscle cells (VSMCs), stimulation with angiotensin II activated RhoA, and this was blocked by pretreatment with 8-bromo-cGMP. VSMCs stimulated by angiotensin II, endothelin-1, or U-46619 significantly increased the phosphorylation levels of both MYPT1 (at Thr696) and CPI-17 (at Thr38). The angiotensin II-induced phosphorylation of MYPT1 was completely blocked by 8-bromo-cGMP or Y-27632 (a Rho-kinase inhibitor), but not by GF109203X (a PKC inhibitor). In contrast, phosphorylation of CPI-17 was inhibited only by GF109203X. Y-27632 dramatically corrected the hypertension in N-omega-nitro-L-arginine methyl ester (L-NAME)treated rats, and this hypertension also was sensitive to isosorbide mononitrate. The level of the active form of RhoA was significantly higher in aortas from L-NAME-treated rats. Expression of RhoA, Rho-kinase, MYPT1, CPI-17, and myosin light chain kinase were not significantly different in aortas from L-NAME-treated and control rats. Activation of RhoA without changes in levels of other signaling molecules were observed in three other rat models of hypertension, ie, stroke-prone spontaneously hypertensive rats, renal hypertensive rats, and DOCA-salt rats. These results suggest that independent of the cause of hypertension, a common point in downstream signaling and a critical component of hypertension is activation of RhoA and subsequent activation of Rho-kinase.