Department of Molecular and Integrative Physiology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
Department of Molecular and Integrative Physiology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
Am J Physiol Cell Physiol. 2014 Jul 1;307(1):C97-106. doi: 10.1152/ajpcell.00337.2013. Epub 2014 Apr 23.
Vascular Gqα signaling has been shown to contribute to cardiac hypertrophy. In addition, angiotensin II (ANG II) was shown to induce vascular smooth muscle cell (VSMC) hypertrophy through Gqα signaling; however, the studies on the role of Gqα and PLC-β1 proteins in VSMC hypertrophy in animal model are lacking. The present study was therefore undertaken to examine the role of Gqα/PLC-β1 proteins and the signaling pathways in VSMC hypertrophy using spontaneously hypertensive rats (SHR). VSMC from 16-wk-old SHR and not from 12-wk-old SHR exhibited enhanced levels of Gqα/PLC-β1 proteins compared with age-matched Wistar-Kyoto (WKY) rats as determined by Western blotting. However, protein synthesis as determined by [(3)H]leucine incorporation was significantly enhanced in VSMC from both 12- and 16-wk-old SHR compared with VSMC from age-matched WKY rats. Furthermore, the knockdown of Gqα/PLC-β1 in VSMC from 16-wk-old SHR by antisense and small interfering RNA resulted in attenuation of protein synthesis. In addition, the enhanced expression of Gqα/PLC-β1 proteins, enhanced phosphorylation of ERK1/2, and enhanced protein synthesis in VSMC from SHR were attenuated by the ANG II AT1 and endothelin-1 (ET-1) ETA receptor antagonists losartan and BQ123, respectively, but not by the ETB receptor antagonist BQ788. In addition, PD98059 decreased the enhanced expression of Gqα/PLC-β1 and protein synthesis in VSMC from SHR. These results suggest that the enhanced levels of endogenous ANG II and ET-1 through the activation of AT1 and ETA receptors, respectively, and MAP kinase signaling, enhanced the expression of Gqα/PLC-β1 proteins in VSMC from 16-wk-old SHR and result in VSMC hypertrophy.
血管 Gqα 信号已被证明有助于心肌肥大。此外，血管紧张素 II（ANG II）通过 Gqα 信号诱导血管平滑肌细胞（VSMC）肥大；然而，关于 Gqα 和 PLC-β1 蛋白在动物模型中 VSMC 肥大中的作用的研究还很缺乏。因此，本研究旨在使用自发性高血压大鼠（SHR）检查 Gqα/PLC-β1 蛋白和信号通路在 VSMC 肥大中的作用。通过 Western blot 分析，与年龄匹配的 Wistar-Kyoto（WKY）大鼠相比，来自 16 周龄 SHR 的 VSMC 表现出增强的 Gqα/PLC-β1 蛋白水平，而来自 12 周龄 SHR 的 VSMC 则没有。然而，与年龄匹配的 WKY 大鼠的 VSMC 相比，来自 12 周龄和 16 周龄 SHR 的 VSMC 的蛋白质合成（通过 [(3)H]亮氨酸掺入确定）显著增强。此外，通过反义寡核苷酸和小干扰 RNA 在 16 周龄 SHR 的 VSMC 中敲低 Gqα/PLC-β1 导致蛋白质合成减弱。此外，血管紧张素 II AT1 和内皮素-1（ET-1）ETA 受体拮抗剂洛沙坦和 BQ123 分别减弱了 SHR 的 VSMC 中 Gqα/PLC-β1 蛋白的增强表达、ERK1/2 的磷酸化增强和蛋白质合成，但 ETB 受体拮抗剂 BQ788 则没有。此外，PD98059 降低了 SHR 的 VSMC 中增强的 Gqα/PLC-β1 和蛋白质合成的表达。这些结果表明，通过分别激活 AT1 和 ETA 受体以及 MAP 激酶信号，增强了 16 周龄 SHR 的 VSMC 中内源性 ANG II 和 ET-1 的水平，导致 Gqα/PLC-β1 蛋白的表达增强，并导致 VSMC 肥大。
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