Bou Daou Grace, Li Yuan, Anand-Srivastava Madhu B
Department of Molecular and Integrative Physiology, Faculty of Medicine, University of Montreal, C.P. 6128, Succ. Centre-ville, Montréal, QC H3C 3J7, Canada.
Can J Physiol Pharmacol. 2016 Jan;94(1):49-58. doi: 10.1139/cjpp-2015-0146. Epub 2015 Jun 18.
Vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit hyperproliferation, enhanced MAP kinase (MAPK) activity, and overexpression of Giα proteins. This study was undertaken to examine whether the overexpression of Giα proteins contributes to the hyperproliferation of VSMC of SHR through MAPK signaling. The hyperproliferation of VSMC from SHR in the absence and presence of angiotensin II was restored towards those in Wistar-Kyoto (WKY) rats levels by pertussis toxin (PT) treatment. In addition, siRNA knockdown of Giα proteins also resulted in the attenuation of hyperproliferation towards control levels. The overexpression of Giα proteins was also inhibited by MAPK and PI3 kinase (PI3K) inhibitors. In addition, the hyperproliferation and enhanced phosphorylation of ERK1/2 and Akt in VSMC from SHR were attenuated towards WKY levels by the inhibitors of MAPK, PI3K, c-Src, and antioxidants, whereas PT was unable to attenuate the enhanced phosphorylation of ERK1/2 and Akt. Furthermore, 8Br-cAMP and forskolin also attenuated the hyperproliferation of VSMC from SHR. These results suggest that the hyperproliferation of VSMC from SHR may be attributed to the enhanced expression of Giα proteins and increased activation of MAPK and PI3 kinase. However, Giα-mediated hyperproliferation may not be mediated through MAPK- and PI3 kinase-dependent pathways and may involve decreased levels of intracellular cAMP.
自发性高血压大鼠（SHR）的血管平滑肌细胞（VSMC）表现出增殖亢进、丝裂原活化蛋白激酶（MAPK）活性增强以及Giα蛋白过表达。本研究旨在探讨Giα蛋白过表达是否通过MAPK信号传导导致SHR的VSMC增殖亢进。通过百日咳毒素（PT）处理，有无血管紧张素II存在时SHR的VSMC增殖亢进恢复至Wistar-Kyoto（WKY）大鼠的水平。此外，Giα蛋白的小干扰RNA（siRNA）敲低也导致增殖亢进减弱至对照水平。MAPK和磷脂酰肌醇-3激酶（PI3K）抑制剂也抑制了Giα蛋白的过表达。此外，MAPK、PI3K、c-Src抑制剂和抗氧化剂使SHR的VSMC中细胞外调节蛋白激酶1/2（ERK1/2）和蛋白激酶B（Akt）的增殖亢进及磷酸化增强减弱至WKY水平，而PT无法减弱ERK1/2和Akt的磷酸化增强。此外，8-溴腺苷酸环化酶（8Br-cAMP）和福斯可林也减弱了SHR的VSMC增殖亢进。这些结果表明，SHR的VSMC增殖亢进可能归因于Giα蛋白表达增强以及MAPK和PI3激酶激活增加。然而，Giα介导的增殖亢进可能不是通过MAPK和PI3激酶依赖性途径介导的，可能涉及细胞内cAMP水平降低。
