Flavonoids (flavones, flavonols, flavanones, and isoflavones) are polyphenols present in many foods of plant origin including citrus fruits, green tea, red wine, and cocoa. Large epidemiological studies link increased consumption of flavonoid- rich foods with reduced cardiovascular morbidity and mortality. However, molecular and physiological mechanisms underlying potential cardiovascular health benefits of flavonoid consumption are poorly understood. The flavanone glycosides hesperidin and naringin are present in citrus fruits. Hesperidin (hesperetin-7-O-rutinoside) is deglycosylated by intestinal microflora in the colon to produce the active aglycone hesperetin, which is then absorbed in the gut and subsequently glucuronidated to hesperetin glucuronide that circulates in plasma. Hesperidin and naringin may have antiinflammatory, hypolipidemic, and vasoprotective properties.
Dyslipidemias contribute to endothelial dysfunction and accelerated atherosclerosis, in part, by promoting imbalances between endothelial-derived vasoconstrictors and vasodilators, growth factors, and pro- and anticoagulant factors. Endothelial dysfunction often manifests as impaired endothelium-dependent vasodilator actions secondary to decreased production and/or bioavailability of nitric oxide (NO).
In human studies, green tea polyphenol epigallocatechin gallate (EGCG; a flavan-3- ol) or polyphenol-rich cocoa intake improves endothelial dysfunction. In the present study, researchers hypothesized that hesperetin, a flavonoid related to EGCG, acutely stimulates production of NO from vascular endothelium to mediate beneficial vascular and antiinflammatory actions in humans.
Rizza S, Muniyappa R, Iantorno M, et al. Citrus Polyphenol Hesperidin Stimulates Production of Nitric Oxide in Endothelial Cells while Improving Endothelial Function and Reducing Inflammatory Markers in Patients with Metabolic Syndrome. J Clin Endocrinol Metab:jc.2010-879. http://jcem.endojournals.org/cgi/content/abstract/jc.2010-2879v1 (Citrus Polyphenol Hesperidin Stimulates Production of Nitric Oxide in Endothelial Cells while Improving Endothelial Function and Reducing Inflammatory Markers in Patients with Metabolic Syndrome -- Rizza et al., 10.1210/jc.2010-2879 -- Journal of Cli)
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 H2O2. Increased adhesion of monocytes to BAEC and expression of vascular cell adhesion molecule-1 in response to TNF- 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.
Dyslipidemias contribute to endothelial dysfunction and accelerated atherosclerosis, in part, by promoting imbalances between endothelial-derived vasoconstrictors and vasodilators, growth factors, and pro- and anticoagulant factors. Endothelial dysfunction often manifests as impaired endothelium-dependent vasodilator actions secondary to decreased production and/or bioavailability of nitric oxide (NO).
In human studies, green tea polyphenol epigallocatechin gallate (EGCG; a flavan-3- ol) or polyphenol-rich cocoa intake improves endothelial dysfunction. In the present study, researchers hypothesized that hesperetin, a flavonoid related to EGCG, acutely stimulates production of NO from vascular endothelium to mediate beneficial vascular and antiinflammatory actions in humans.
Rizza S, Muniyappa R, Iantorno M, et al. Citrus Polyphenol Hesperidin Stimulates Production of Nitric Oxide in Endothelial Cells while Improving Endothelial Function and Reducing Inflammatory Markers in Patients with Metabolic Syndrome. J Clin Endocrinol Metab:jc.2010-879. http://jcem.endojournals.org/cgi/content/abstract/jc.2010-2879v1 (Citrus Polyphenol Hesperidin Stimulates Production of Nitric Oxide in Endothelial Cells while Improving Endothelial Function and Reducing Inflammatory Markers in Patients with Metabolic Syndrome -- Rizza et al., 10.1210/jc.2010-2879 -- Journal of Cli)
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 H2O2. Increased adhesion of monocytes to BAEC and expression of vascular cell adhesion molecule-1 in response to TNF- 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.