Abstract 3392: Resveratrol Regulates Pro-oxidative And Anti-oxidative Enzymes In The Cardiovascular System
Resveratrol is likely to contribute to the potential of red wine in preventing human cardiovascular disease. In addition to its (moderate) direct antioxidant effect, we have found that resveratrol also regulates pro-oxidative and anti-oxidative enzymes in vivo. Atherosclerotic apolipoprotein E knockout (apoE-KO) mice were treated orally with resveratrol (30 or 100 mg/kg/day for 7 days). mRNA expression of NADPH oxidases, xanthine oxidase and superoxide dismutase (SOD) isoforms was analyzed with quantitative real-time RT-PCR. Resveratrol had little effect on the mRNA expression of NADPH oxidases or xanthine oxidase in the heart of apo-KO mice. However, resveratrol inhibited translocation of Rac1 and p47phox from cytosol to membrane and thus attenuated the activity of NADPH oxidase enzyme complex. Cardiac expression of SOD isoforms was increased significantly by resveratrol at both mRNA and protein levels. This was associated with reduced superoxide content in the heart of apoE-KO mice. Cardiac content of malondialdehyde (MDA), an indicators of lipid peroxidation and a biomarker for oxidative stress, was reduced by resveratrol treatment. ApoE-KO mice are an animal model of oxidative stress and the endothelial nitric oxide synthase (eNOS) was found in an uncoupled state, producing superoxide instead of NO. This was probably due to a relative deficiency of (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4), the essential cofactor of eNOS, which is sensitive to oxidation. Resveratrol treatment significantly increased BH4 levels in the heart. The mRNA of GTP cyclohydrolase 1, the rate-limiting enzyme for the de novo synthesis of BH4, was not changed by resveratrol, suggesting that the BH4 enhancement was due to reduced oxidation rather than increased production. By enhancing BH4 content, resveratrol reversed eNOS uncoupling and reduced superoxide production by eNOS. In conclusion, resveratrol reduced oxidative stress in atherosclerotic apoE-KO mice by inhibiting NADPH oxidase activity, upregulating SOD isoforms, and reverting eNOS uncoupling. This appears as a promising profile for the prevention or treatment of cardiovascular disease.