Up-regulation of endothelial nitric oxide synthase (eNOS), silent mating type information regulation 2 homologue 1 (SIRT1) and autophagy-related genes by repeated treatments with resveratrol in human umbilical vein endothelial cells

Abstract

Resveratrol, a polyphenolic phytoalexin found in red wine and various plants, has been reported to up-regulate the expression of endothelial NO synthase (eNOS) in human umbilical vein endothelial cells (HUVEC). However, this effect was neither long term in nature nor physiologically relevant at the concentration of resveratrol studied. In the present study, we investigated the effects of repeated treatments with a lower concentration of resveratrol on the expression of genes in HUVEC. The expression levels of eNOS and silent mating type information regulation 2 homologue 1 (SIRT1) were up-regulated in HUVEC by repeated treatments with 1 mM-resveratrol for 6 d, but not with fenofibrate. Moreover, resveratrol treatment increased the expression of autophagy-regulated genes such as g-aminobutyric acid A receptor-associated protein (GABARAP), microtubule-associated protein 1 light chain 3B (LC3B) and autophagy-related protein 3 (ATG3), the radical scavenger activity-related metallothionein-1X (MT1X) gene and the anti-inflammatory activity-related annexin A2 (ANXA) gene. In addition, resveratrol treatment down-regulated the expression of the cell-cycle checkpoint control RAD9 homologue B (RAD9B) gene. These results indicate the beneficial effects of resveratrol on the cardiovascular system. Key words: Resveratrol: Endothelial nitric oxide synthase: Silent mating type information regulation 2 homologue 1: AutophagyThe prevention of lifestyle-related diseases such as CVD, diabetes and stroke has attracted worldwide interest. Current treatment regimens for lifestyle-related diseases have shifted their focus onto the functionality of natural chemicals present in foods and drinks. One example is the association between the long-term consumption of red wine and reduced risk for CVD. In this context, resveratrol, a phytoalexin and antioxidant polyphenol present in red wine and various plants, has emerged as one of the most attractive and extensively studied compounds (1,2) .We have previously demonstrated that resveratrol suppresses the expression of cyclo-oxygenase (COX)-2, the rate-limiting enzyme in PG biosynthesis (3) , particularly in 184B5/ HER(184B5/human EGFR-related-2)-transformed mammary epithelial cells (4) . Additionally, we have shown that resveratrol activates PPARa, PPARbd and PPARg (5,6) , which are members of the nuclear receptor family of ligand-dependent transcription factors (7,8) ; that it protects the brain against ischaemic stroke in mice through a PPARa-dependent mechanism demonstrated in cell-based reporter assays (5) and that it acts via a negative feedback loop mediated through PPARg to inhibit the expression of COX-2, particularly in macrophages (9) . Based on these data, we have focused our attention on PPAR as potential molecular targets of resveratrol in the prevention of lifestyle-related diseases, the molecular mechanisms of which remain to be determined.Previous studies have investigated the effects of resveratrol on the activation of silent mating type information regulation 2 homol...

At the interface of antioxidant signalling and cellular function: Key polyphenol effects

“…Other studies also showed that 2.5 mg/kg body wt/day of resveratrol for 15 days ameliorated endothelial dysfunction by regulating VEGF, eNOS, caveolin‐1 and haem oxygenase (HO)‐1 in diabetic rats, while a dose of 20 mg/kg resveratrol for two weeks led to neovascularization of the hyper‐cholesterolaemic myocardium of rats and conferred protection against myocardial injury caused by ischemia‐reperfusion through the same mechanism . These studies are only a few of many other animal studies and others in vitro in the literature showing beneficial effects of resveratrol in the endothelium through NO‐related mechanisms .…”

Calorie restriction and sirtuins revisited

“…Inhibition of this SIRT1 induction sensitizes ECs to damage inflicted by oxidized LDL (Guo et al 2013) and sensitizes apoE À/À mice to atherosclerosis (Zhang et al 2008). The SIRT1/AMPK axis in ECs has been shown to be inducible by exercise or resveratrol in mice (Cacicedo et al 2011;Takizawa et al 2013).…”

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“…11 | P a g e SIRT1, and several genes related to autophagy including LC3B and AGT3 (Chen et al, 2013;Takizawa et al, 2013). In support of such protective effects, RV has also been shown to preserve telomere length and increase telomerase activity in aortic rings from aged rats (da Luz et al, 2012a).…”