Activation of the D4 dopamine receptor attenuates proliferation and migration of vascular smooth muscle cells through downregulation of AT1a receptor expression.
Activation of the D4 dopamine receptor attenuates proliferation and migration of vascular smooth muscle cells through downregulation of AT1a receptor expression.
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D-4 多巴胺受体的激活通过下调 AT(1a) 受体表达来减弱血管平滑肌细胞的增殖和迁移
DOI：
10.1038/hr.2015.48
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Zeng C
中科院分区：
文献类型：
--
作者：
Yu C;Chen J;Guan W;Han Y;Wang WE;Wang X;Wang H;Jose PA;Zeng C
血管紧张素（Angiotensin，Ang）II在血管平滑肌细胞（VSMC）的增殖和迁移以及随后的血管疾病的发展中具有重要作用，而多巴胺具有相反的作用。以前的研究表明，多巴胺和AT 1受体之间的相互作用在肾脏。多巴胺D4受体在动脉中表达，对VSMC增殖具有抑制作用。我们推测，D4受体，通过其与AT 1a受体的相互作用，可能对血管紧张素II介导的VSMC增殖和迁移，这可能有一个高血压诱导的血管重塑的关键作用的抑制作用。在本研究中，我们发现，Ang II显着诱导A10细胞的增殖和迁移，这是由D4受体激动剂PD 168077抑制。PD 168077对D4受体的激活以浓度和时间依赖性方式抑制AT 1a受体的表达。通过用D4受体靶向小干扰RNA沉默D4受体来减弱这些作用。D4受体介导的AT 1受体功能抑制涉及蛋白激酶A（PKA）。PD 168077对D4受体的激活增加了A10细胞中PKA的活性，PKA抑制剂（PKA抑制剂14-22，10−7 mol l−1/24 h）的存在阻断了D4受体对AT 1受体表达和功能的抑制作用。相对于来自Wistar-Kyoto大鼠的VSMCs，来自自发性高血压大鼠的VSMCs（原代培养物）中保留了D4受体对AT 1受体表达和功能的抑制作用。总之，我们的数据提供了深入了解的D4受体的AT 1a受体的表达和功能的VSMCs的调节作用，并建议，针对D4受体的作用可能代表一种有效的治疗方法，用于治疗心血管疾病。
Angiotensin (Ang) II has an important role in the vascular smooth muscle cell (VSMC) proliferation and migration and subsequently in the development of vascular diseases, whereas dopamine has the opposite effect. Previous studies have shown an interaction between dopamine and AT1 receptors in the kidney. The dopamine D4 receptor is expressed in arteries and has an inhibitory effect on VSMC proliferation. We hypothesized that the D4 receptor, through its interaction with the AT1a receptor, may have an inhibitory effect on Ang II-mediated VSMC proliferation and migration, which could have a pivotal role in hypertension-induced vascular remodeling. In the current study, we found that Ang II markedly induced the proliferation and migration of A10 cells, which was inhibited by the D4 receptor agonist PD168077. The activation of the D4 receptor by PD168077 inhibited AT1a receptor expression in a concentration- and time-dependent manner. These effects were attenuated by silencing the D4 receptor with a D4 receptor-targeting small interfering RNA. The D4 receptor-mediated inhibition of AT1 receptor function involved protein kinase A (PKA). The activation of the D4 receptor by PD168077 increased PKA activity in A10 cells, and the presence of a PKA inhibitor (PKA inhibitor 14–22, 10−7 mol l−1 per 24h) blocked the inhibitory effect of the D4 receptor on AT1 receptor expression and function. The inhibitory effect of the D4 receptor on AT1 receptor expression and function was preserved in VSMCs (primary culture) from spontaneously hypertensive rats relative to VSMCs from Wistar-Kyoto rats. In conclusion, our data provide insight into the regulatory role of the D4 receptor on AT1a receptor expression and function in VSMCs and suggest that targeting the action of the D4 receptor may represent an effective therapeutic approach for the treatment of cardiovascular diseases.
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影响因子：
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作者：
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