The angiotensin II receptor antagonist, losartan, enhances regulator of G protein signaling 2 mRNA expression in vascular smooth muscle cells of Wistar rats
The angiotensin II receptor antagonist, losartan, enhances regulator of G protein signaling 2 mRNA expression in vascular smooth muscle cells of Wistar rats
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血管紧张素 II 受体拮抗剂氯沙坦增强 Wistar 大鼠血管平滑肌细胞中 G 蛋白信号调节因子 2 mRNA 的表达
DOI：
10.1038/hr.2015.154
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发表时间：
2016
期刊：
影响因子：
5.4
通讯作者：
Uehara Y.
中科院分区：
文献类型：
--
作者：
Wu Y;Nakagawa S;Takahashi H;Kawabata Y;Suzuki E;Uehara Y.
据报道，血管紧张素II（Ang II）增强G蛋白信号转导2（RGS2）的调节剂，从而形成Ang II信号转导的负反馈环。然而，很少有研究报告是否血管紧张素II受体（ATR）拮抗剂影响RGS2 mRNA的表达。我们使用雄性Wistar大鼠胸主动脉的血管平滑肌细胞研究了当用Ang II亚型1受体（AT 1 R）阻断剂阻断Ang II与ATR结合时RGS2 mRNA的表达。RGS2 mRNA表达显著增加与Ang II刺激，这种增加几乎完全消除奥美沙坦，一个有效的AT 1 R特异性阻断剂。血管紧张素Ⅱ 2型受体（AT2R）不参与血管紧张素Ⅱ介导的RGS表达.与此相反，AT1R阻断剂氯沙坦部分降低Ang II介导的RGS2mRNA表达，因为这种拮抗剂直接刺激无Ang II培养基中RGS2mRNA的表达。EXP3174是氯沙坦的活性代谢物，几乎完全减弱Ang II介导的RGS2 mRNA表达，而不直接刺激RGS2 mRNA表达。奥美沙坦预处理可抑制Ang II介导的RGS2 mRNA表达。用蛋白激酶C抑制剂治疗部分降低了氯沙坦介导的RGS2 mRNA表达。这些结果表明，AT1R阻断剂通过AT1R介导的机制抑制Ang Ⅱ诱导的RGS2mRNA表达。然而，AT1 R阻断剂氯沙坦通过蛋白激酶C依赖性和非依赖性途径，通过AT1 R作为RGS2 mRNA表达的直接激动剂。结论：氯沙坦对RGS2 mRNA表达具有双重作用，直接上调RGS2 mRNA表达可能为高血压的治疗提供新的策略。
Angiotensin II (Ang II) reportedly enhances regulator of G-protein signaling 2 (RGS2), thus making a negative feedback loop for Ang II signal transduction. However, few studies have reported whether Ang II receptor (ATR) antagonists influence RGS2 mRNA expression. We investigated RGS2 mRNA expression when Ang II binding to ATR was blocked with Ang II subtype-1 receptor (AT 1 R) blockers using vascular smooth muscle cells from the thoracic aorta of male Wistar rats. RGS2 mRNA expression significantly increased with Ang II stimulation, and this increase was almost completely abolished by olmesartan, a potent AT 1 R-specific blocker. Ang II subtype-2 receptor (AT 2 R) was not involved in Ang II-mediated RGS expression. In contrast, the AT 1 R blocker, losartan, partially decreased Ang II-mediated RGS2 mRNA expression because this antagonist directly stimulated RGS2 mRNA expression in Ang II-free medium. EXP3174, which is an active metabolite of losartan, almost completely blunted Ang II-mediated RGS2 mRNA expression without direct stimulation of RGS2 mRNA expression. Moreover, pretreatment with olmesartan abolished Ang II-mediated RGS2 mRNA expression. Treatment with a protein kinase C inhibitor partially decreased losartan-mediated RGS2 mRNA expression. These results suggest that AT 1 R blockers inhibit RGS2 mRNA expression in response to Ang II via an AT 1 R-mediated mechanism. However, the AT 1 R blocker, losartan, behaves as a direct agonist for RGS2 mRNA expression via AT 1 R through protein kinase C-dependent and-independent pathways. In conclusion, losartan exhibits dual effects on RGS2 mRNA expression, and the direct upregulation of RGS2 mRNA expression may provide a new strategy for the treatment of hypertension.