Effects of citrus flavonoids on endothelial function and cardiovascular health

Cardiovascular diseases (CVD) represent one of the leading causes of mortality worldwide. Epidemiological studies have suggested an inverse association between the consumption of citrus fruit and the risk of CVD. However, the molecular mechanisms by which citrus flavonoids contribute to cardiovascular health have not been fully elucidated. In addition, evidence from human studies is limited and contradictory. Therefore, the aims of this thesis were to investigate mechanisms by which citrus flavonoids impact on endothelial cells and their effects on endothelial function and cardiovascular health in an acute manner and following regular consumption. The potential of selected citrus flavonoids to modulate gene expression relevant to nitric oxide (NO) production and antioxidant status was investigated in EA.hy926 cells; the acute effect of flavanone-rich blond orange juice (total flavanone content=81.7 mg/100 ml) on vascular function (cardiac electrical activity, blood pressure, vascular compliance, peripheral blood flow, pulse transit time and pulse wave velocity) in healthy subjects (n=13) was determined; in a randomized controlled crossover trial, the effect of flavanone-rich blood orange juice (total flavanone content=89.7 mg/100 ml) on endothelial function, blood pressure, lipid profile, inflammation in overweight/obese men and premenopausal women of European origin (n=15) were examined following 2-week consumption (400 ml/d) of blood orange juice and a sugar-matched control drink. The in vitro study demonstrates NOS3 mRNA and protein expression were significantly upregulated by nobiletin and tangeretin; incubation with nobiletin also resulted in a significant reduction in ET-1 mRNA levels and a significant induction of HO-1 and GCLC. Vascular related markers were not acutely altered at 2 h post consumption of a flavanone-rich orange juice in healthy subjects under the investigated conditions. Following 2-week consumption of blood orange juice, endothelial function was significantly improved from 8.15% ± 2.92% to 10.16% ± 3.31%, compared to the control drink (time by treatment interaction: P=0.002). Interestingly, this favourable effect on endothelial function was only observed in overweight subjects but not in obese subjects. Baseline blood pressure, lipid profile, hsCRP and ET-1 were generally within healthy ranges and not altered during juice supplementation. Present data indicate that regular consumption of blood orange juice exerts beneficial effect on endothelial function in healthy overweight men and premenopausal women of European origin, which may be attributed to elevated NO bioavailability and the induction of cell-protective enzymes as evidenced by the in vitro findings.