Red Wine Polyphenolic Compounds Inhibit Vascular Endothelial Growth Factor Expression in Vascular Smooth Muscle Cells by Preventing the Activation of the p38 Mitogen-Activated Protein Kinase Pathway

Abstract

Objective-Moderate consumption of red wine has a beneficial effect on the cardiovascular system. This study examines whether red wine polyphenolic compounds (RWPCs) affect vascular endothelial growth factor (VEGF) expression, a major angiogenic and proatherosclerotic factor in vascular smooth muscle cells (VSMCs). Methods and Results-VEGF mRNA expression was assessed by Northern blot analysis and the release of VEGF by immunoassay in cultured VSMCs. Short-term and long-term exposure of VSMCs to RWPCs inhibited VEGF mRNA expression and release of VEGF in response to platelet-derived growth factor AB (PDGF AB ), transforming growth factor-␤ 1 , or thrombin. The PDGF AB -induced expression of VEGF was markedly reduced by SB203580 (inhibitor of p38 mitogen-activated protein kinase [MAPK]), antioxidants, and diphenylene iodonium (inhibitor of flavin-dependent enzymes), slightly reduced by PD98059 (inhibitor of MEK), and not significantly affected by wortmannin (inhibitor of PI-3-kinase) and L-JNKI (inhibitor of JNK). Short-term and long-term treatment of VSMCs with RWPCs markedly reduced PDGF AB -induced production of reactive oxygen species and phosphorylation of p38 MAPK. Conclusions-These data indicate that RWPCs strongly inhibit growth factor-induced VEGF expression in VSMCs bypreventing the redox-sensitive activation of the p38 MAPK pathway. The potential antiangiogenic and antiatherosclerotic properties of RWPCs are likely to contribute to cardiovascular protection by preventing the development of atherosclerotic lesions. Key Words: red wine polyphenolic compounds Ⅲ vascular endothelial growth factor Ⅲ vascular smooth muscle cells Ⅲ atherosclerosis Ⅲ angiogenesis E pidemiological studies have suggested that light to moderate consumption of alcoholic beverages, particularly red wine, is associated with a reduction in overall mortality, and this effect is attributable primarily to a reduced risk of coronary heart disease. 1,2 Although the exact nature of the protective effect of red wine on coronary diseases is unclear, it might be attributable, in part, to its ability to reduce the progression of early atherosclerotic lesions, as observed in human coronary arteries at childhood, to advanced plaques, which are prone to rupture with superimposed thrombosis. This is consistent with the findings that the consumption of red wine reduced the progression of lesions in experimental models of atherosclerosis. [3][4][5] The protective effect of red wine seems to be attributable, at least in part, to polyphenols, because nonalcoholic wine products and the red wine polyphenolic compounds (RWPCs) quercetin and catechin also prevented the progression of atherosclerotic lesions. [3][4][5] The beneficial effect of RWPCs might be related to their ability to prevent oxidation of LDL, 6 activation of platelets, 7 and expression of tissue factor and monocyte chemoattractant protein-1. 8,9 Recent findings have indicated that vascular endothelial growth factor (VEGF) is strongly expressed in human atherosclerotic plaques. 10,11 The c...

Raf and MEK Protein Kinases Are Direct Molecular Targets for the Chemopreventive Effect of Quercetin, a Major Flavonol in Red Wine

“…RWE was kindly provided by Dr. Schini-Kerth (Universite Louis Pasteur, Strasbourg, France). The procedure used to prepare RWE has been described previously (20). In brief, phenolic compounds were adsorbed onto a preparative column, the alcohol was desorbed, the alcoholic eluent was gently evaporated, and finally the concentrated residue was lyophilized and finely sprayed to obtain RWE dry powder.…”

Catalyser-21TM, a mineral water derived from leaf soil, inhibits tumor cell invasion and angiogenesis

“…Using HeLa and HT1080 cells, our results indicate that Catalyser-21 TM does indeed have anticancer effects via reduction of VEGF and of MMP-2 gene transcription and protein secretion. In recent years, natural antioxidants in foodstuffs have attracted much attention because of their health-promoting and disease-preventing effects, including cancers (Jung et al 2001;Oak et al 2003Oak et al , 2005Tang et al 2006). A mixture of green tea extract, vitamin E, and several amino acids was shown to reduce the development of cancer and metastasis by suppressing MMP TM .…”

Red Wine Polyphenols Prevent Acceleration of Neovascularization by Angiotensin II in the Ischemic Rat Hindlimb

“…Thus, RWPs and anthocyanins contained in red wine inhibit the induction of VEGF expression in vascular smooth muscle cells by several growth factors (Oak et al, 2003. RWPs also prevent the activation by growth factors of MMP-2, a collagenase involved in the angiogenic process (Oak et al, 2004).…”

“…In addition, RWPs also prevent vascular smooth muscle cell migration and proliferation via the inhibition of the p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways (Iijima et al, 2002). Moreover, RWPs inhibit the expression of VEGF and matrix metalloproteinase type II (MMP-2), two major proangiogenic factors, in vascular smooth muscle cells (Oak et al, 2003;2004). Furthermore, RWPs prevent in vivo the Ang II-induced expression of VEGF and MMP-2 in the aortic wall (Walter et al, 2008).…”