Ungvari Zoltan, Orosz Zsuzsanna, Rivera Aracelie, Labinskyy Nazar, Xiangmin Zhao, Olson Susan, Podlutsky Andrej, Csiszar Anna
Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
Am J Physiol Heart Circ Physiol. 2007 May;292(5):H2417-24. doi: 10.1152/ajpheart.01258.2006. Epub 2007 Jan 12.
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-alpha elicited significant increases in caspase-3/7 activity in endothelial cells and cultured rat aortas, which were prevented by resveratrol pretreatment (10(-6)-10(-4) 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(2)O(2) levels and H(2)O(2)-mediated apoptotic cell death induced by oxidative stressors (exogenous H(2)O(2), 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 H(2)O(2) in vitro. Thus resveratrol seems to increase vascular oxidative stress resistance by scavenging H(2)O(2) 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.
流行病学研究表明，富含白藜芦醇的地中海饮食与冠状动脉疾病风险降低有关。然而，白藜芦醇发挥血管保护作用的机制尚未完全明确。由于氧化应激和内皮细胞损伤在血管衰老和动脉粥样硬化形成中起关键作用，我们评估了白藜芦醇是否能抑制氧化应激诱导的内皮细胞凋亡。我们发现，氧化型低密度脂蛋白和肿瘤坏死因子-α可使内皮细胞和培养的大鼠主动脉中caspase-3/7活性显著增加，而白藜芦醇预处理（10⁻⁶ - 10⁻⁴ mol/l）可预防这种增加。谷胱甘肽过氧化物酶和血红素加氧酶-1的抑制可减弱白藜芦醇的保护作用，提示抗氧化系统在白藜芦醇的抗凋亡作用中发挥作用。事实上，白藜芦醇处理可保护培养的主动脉节段和/或内皮细胞，使其免受氧化应激源（外源性过氧化氢、百草枯和紫外线）诱导的细胞内过氧化氢水平升高和过氧化氢介导的凋亡细胞死亡。白藜芦醇处理还可减轻紫外线诱导的DNA损伤（彗星试验）。白藜芦醇处理可上调培养动脉中谷胱甘肽过氧化物酶、过氧化氢酶和血红素加氧酶-1的表达，而对超氧化物歧化酶同工型的表达无显著影响。白藜芦醇在体外也能有效清除过氧化氢。因此，白藜芦醇似乎通过清除过氧化氢和防止氧化应激诱导的内皮细胞死亡来增加血管对氧化应激的抵抗力。我们认为，白藜芦醇的抗氧化和抗凋亡作用，连同其先前描述的抗炎作用，至少部分地解释了其心脏保护作用。
