Abstract-Proliferation of pulmonary arterial smooth muscle cells, endothelial dysfunction, oxidative stress, and inflammation promotes the development of pulmonary hypertension. Resveratrol is a polyphenolic compound that exerts antioxidant and anti-inflammatory protective effects in the systemic circulation, but its effects on pulmonary arteries remain poorly defined. The present study was undertaken to investigate the efficacy of resveratrol to prevent pulmonary hypertension. Rats injected with monocrotaline progressively developed pulmonary hypertension. Resveratrol treatment (25 mg/kg per day, PO, from day 1 postmonocrotaline) attenuated right ventricular systolic pressure and pulmonary arterial remodeling, decreased expression of inflammatory cytokines (tumor necrosis factor-␣, interleukin 1␤, interleukin 6, and platelet-derived growth factor-␣/␤), and limited leukocyte infiltration in the lung. Resveratrol also inhibited proliferation of pulmonary arterial smooth muscle cells. Treatment of rats with resveratrol increased expression of endothelial NO synthase, decreased oxidative stress, and improved endothelial function in small pulmonary arteries. Pulmonary hypertension was associated with an upregulation of NAD(P)H oxidase in small pulmonary arteries, which was significantly attenuated by resveratrol treatment. Our studies show that resveratrol exerts anti-inflammatory, antioxidant, and antiproliferative effects in the pulmonary arteries, which may contribute to the prevention of pulmonary hypertension. Key Words: pulmonary hypertension Ⅲ resveratrol Ⅲ oxidative stress Ⅲ endothelial dysfunction Ⅲ inflammation P ulmonary hypertension is a syndrome that encompasses several diseases, all of which have in common increased pulmonary artery pressures. Idiopathic ("primary") pulmonary hypertension is a rare disease caused by genetic defects in the bone morphogenetic protein signaling pathways. Common causes of "secondary" forms of pulmonary hypertension include the following: (1) pulmonary hypertension associated with chronic obstructive pulmonary disease; (2) pulmonary embolism; and (3) pressure/volume overload-related pulmonary hypertension. In addition, pulmonary hypertension often develops in patients with autoimmune diseases or as a severe adverse effect of anorectic drug treatment. Despite the diverse etiologic differences, many similarities in the pathological alterations in pulmonary arteries occur among the various forms of pulmonary hypertension, ie, vascular remodeling, including cellular proliferation in both the intima and media; endothelial dysfunction/increased vasoconstriction; and activation of inflammatory processes (eg, inflammatory cytokine expression and monocyte infiltration).Current therapies for chronic pulmonary hypertension are designed to reduce pulmonary arterial resistance by inducing vasodilation (eg, NO inhalation, stimulation of cGMP production by phosphodiesterase inhibitors, endothelin receptor antagonists, and prostacyclin analogs). These therapeutic approaches mainly provide ...

Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. However, the mechanisms by which resveratrol exerts its vasculoprotective effects are not completely understood. Because oxidative stress and endothelial cell injury play a critical role in vascular aging and atherogenesis, we evaluated whether resveratrol inhibits oxidative stress-induced endothelial apoptosis. We found that oxidized LDL and TNF-␣ elicited significant increases in caspase-3/7 activity in endothelial cells and cultured rat aortas, which were prevented by resveratrol pretreatment (10 Ϫ6 -10 Ϫ4 mol/l). The protective effect of resveratrol was attenuated by inhibition of glutathione peroxidase and heme oxygenase-1, suggesting a role for antioxidant systems in the antiapoptotic action of resveratrol. Indeed, resveratrol treatment protected cultured aortic segments and/or endothelial cells against increases in intracellular H 2O2 levels and H2O2-mediated apoptotic cell death induced by oxidative stressors (exogenous H 2O2, paraquat, and UV light). Resveratrol treatment also attenuated UV-induced DNA damage (comet assay). Resveratrol treatment upregulated the expression of glutathione peroxidase, catalase, and heme oxygenase-1 in cultured arteries, whereas it had no significant effect on the expression of SOD isoforms. Resveratrol also effectively scavenged H2O2 in vitro. Thus resveratrol seems to increase vascular oxidative stress resistance by scavenging H2O2 and preventing oxidative stress-induced endothelial cell death. We propose that the antioxidant and antiapoptotic effects of resveratrol, together with its previously described anti-inflammatory actions, are responsible, at least in part, for its cardioprotective effects. endothelial cell; comet assay; caloric restriction mimetics; apoptosis; polyphenol; heme oxygenase antioxidant EPIDEMIOLOGICAL STUDIES have shown that, in southern France and other Mediterranean territories, the morbidity and mortality of coronary artery disease is low, despite a diet rich in saturated fats and smoking habits (17,30). This unexpected epidemiological finding was termed the "French paradox." It has been proposed that resveratrol, an important constituent of Mediterranean diets, is involved in vasculoprotection. Resveratrol has been identified in more than 70 species of plants, including grapevines (Vitis vinifera), mulberries (Morus rubra), Vaccinum species, and peanuts (Arachis hypogea), and it is thought to have diverse antiatherogenic activities (42, 55-57, 60, 61), such as the inhibition of LDL oxidation (22) and platelet aggregation (46) and regulation of vascular smooth muscle proliferation (24 -26, 54). Recently, studies from this and other laboratories have shown that resveratrol inhibits endothelial activation and monocyte adhesion (12, 21, 39) and attenuates proinflammatory gene expression by inhibition of NF-B activation in coronary arterial endothelial cells (12).There is overwhelming evidence that oxidative stres...

Protein kinase C (PKC) stimulation of NAD(P)H oxidases (Nox) is an important component of multiple vascular disease processes; however, the relationship between oxidase activation and the regulation of vascular smooth muscle contraction by PKC remains poorly understood. Therefore, we examined the signaling cascade of PKC-elicited Nox activation and the role of superoxide and hydrogen peroxide in mediating PKC-induced vascular contraction. Endothelium-denuded bovine coronary arteries showed a PKC-dependent basal production of lucigenin (5 muM)-detected Nox oxidase-derived superoxide, which was stimulated fourfold by PKC activation with 10 muM phorbol 12,13-dibutyrate (PDBu). PDBu appeared to increase superoxide generation by Nox2 through both p47(phox) and peroxide-dependent Src activation mechanisms based on the actions of inhibitors, properties of Src phosphorylation, and the loss of responses in aorta from mice deficient in Nox2 and p47(phox). The actions of inhibitors of contractile regulating mechanisms, scavengers of superoxide and peroxide, and responses in knockout mouse aortas suggest that a major component of the contraction elicited by PDBu appeared to be mediated through peroxide derived from Nox2 activation stimulating force generation through Rho kinase and calmodulin kinase-II mechanisms. Superoxide generated by PDBu also attenuated relaxation to nitroglycerin. Peroxide-derived from Nox2 activation by PKC appeared to be a major contributor to the thromboxane A(2) receptor agonist U46619 (100 nM)-elicited contraction of coronary arteries. Thus a p47(phox) and Src kinase activation of peroxide production by Nox2 appears to be an important contributor to vascular contractile mechanisms mediated through activation of PKC.