The Effect of Resveratrol on the Hyperproliferation of Vascular Smooth Muscle Cells from Spontaneously Hypertensive Rats : Molecular Mechanisms
Vascular remodeling due to the hyperproliferation and hypertrophy of vascular smooth muscle cells (VSMCs) is central in the development of hypertension. VSMCs from spontaneously hypertensive rats (SHR) exhibit hyperproliferation and overexpression of cell cycle proteins. Resveratrol, a natural polyphenolic compound found in the skin of grapes, is implicated in several vasoprotective effects. Resveratrol has also been reported to attenuate angiotensin II-induced VSMCs proliferation. However, it was not elucidated if resveratrol could also inhibit the hyperproliferation of VSMCs from SHR. The present study was undertaken to investigate if resveratrol could attenuate the hyperproliferation of VSMCs and explore the underlying molecular mechanisms responsible for this effect. Methods: For this study, aortic VSMCs from 14-week-old SHR and Wistar-Kyoto (WKY) rats were used. The proliferation of VSMCs was determined by [3H] thymidine incorporation and the levels of proteins were determined by Western blotting techniques. Results: VSMCs from SHR exhibit a hyperproliferation which was attenuated by resveratrol. The overexpression of cyclin D1, cyclin E, cyclin dependent kinase 4 (CDK4), cyclin dependent kinase 2 (CDK2), phosphorylated retinoblastoma protein (pRb), Giα-3, Giα-2 proteins and enhanced phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and AKT in VSMCs from SHR were attenuated by resveratrol. Furthermore, resveratrol also inhibited the increase of the superoxide anion, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, overexpression of NADPH oxidase 2 (NOX2)/NADPH oxidase 4 (NOX4) and P47phox proteins, and the increased phosphorylation of epidermal growth factor receptor (EGF-R), insulin-like growth factor 1 receptor (IGF-1R), and c-Src to control levels. These results suggest that resveratrol through the inhibition of reactive oxygen species (ROS) and ROS-mediated transactivation of growth factor receptors, c-Src, mitogen-activated protein kinases (MAPK)/Phosphoinositide-3 kinase (PI3K), attenuates the overexpression of Giα and cell cycle proteins and results in the attenuation of hyperproliferation of VSMCs from SHR.
Hypertension Resveratrol VSMCs proliferation Cell cycle proteins MAPK PI3K Giα proteins Oxidative stress SHR Growth factor receptors c-Src