Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome.

CONTEXT: Hesperidin, a citrus flavonoid, and its metabolite hesperetin may have vascular actions relevant to their health benefits. Molecular and physiological mechanisms of hesperetin actions are unknown. OBJECTIVE: We tested whether hesperetin stimulates production of nitric oxide (NO) from vascular endothelium and evaluated endothelial function in subjects with metabolic syndrome on oral hesperidin therapy. DESIGN, SETTING, AND INTERVENTIONS: Cellular mechanisms of action of hesperetin were evaluated in bovine aortic endothelial cells (BAEC) in primary culture. A randomized, placebo-controlled, double-blind, crossover trial examined whether oral hesperidin administration (500 mg once daily for 3 wk) improves endothelial function in individuals with metabolic syndrome (n = 24). MAIN OUTCOME MEASURE: We measured the difference in brachial artery flow-mediated dilation between placebo and hesperidin treatment periods. RESULTS: Treatment of BAEC with hesperetin acutely stimulated phosphorylation of Src, Akt, AMP kinase, and endothelial NO synthase to produce NO; this required generation of H(2)O(2). Increased adhesion of monocytes to BAEC and expression of vascular cell adhesion molecule-1 in response to TNF-α treatment was reduced by pretreatment with hesperetin. In the clinical study, when compared with placebo, hesperidin treatment increased flow-mediated dilation (10.26 ± 1.19 vs. 7.78 ± 0.76%; P = 0.02) and reduced concentrations of circulating inflammatory biomarkers (high-sensitivity C-reactive protein, serum amyloid A protein, soluble E-selectin). CONCLUSIONS: Novel mechanisms for hesperetin action in endothelial cells inform effects of oral hesperidin treatment to improve endothelial dysfunction and reduce circulating markers of inflammation in our exploratory clinical trial. Hesperetin has vasculoprotective actions that may explain beneficial cardiovascular effects of citrus consumption.

Pioglitazone improves endothelial and adipose tissue dysfunction in pre-diabetic CAD subjects.

OBJECTIVE: To investigate the effect of pioglitazone on endothelial and adipose tissue dysfunction in newly detected IGT patients with CAD. METHODS AND DESIGN: Participants (n=25) were randomized to treatment with either placebo or pioglitazone (30 mg/day) for 12 weeks. Before and after treatment we evaluated endothelial function (flow-mediated dilation--FMD--of the brachial artery), circulating adipose and inflammatory markers (adiponectin isoforms, TNF-alpha, and high sensitivity-CRP), and insulin sensitivity (euglycemic hyperinsulinemic clamp). RESULTS: No significant changes were observed in subjects (n=12) treated with placebo. By contrast, subjects (n=13) treated with pioglitazone had significant improvement in FMD (10.8±5.3 vs 13.3±3.6%, p<0.01), accompanied by increased high molecular weight adiponectin (HMW-Ad) (1.7±1.2 vs 4.8±3.6 µg/ml, p<0.05) and decreased TNF-alpha (4.3±1.9 vs 3.2±1.2 pg/ml, p<0.05) associated to an increased glucose disposal (4.8±1.9 vs 5.4±2.0 mg kg(-1) min(-1), p<0.05). A multiple regression analysis indicated that increasing of HMW-Ad after pioglitazone predicted increased FMD. CONCLUSION: Pioglitazone significantly improves endothelial and adipose tissue dysfunction in pre-diabetic patients with CAD.