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

Abstract

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.

• Authors: Stefano Rizza, Ranganath Muniyappa, Micaela Iantorno, Jeong-a Kim, Hui Chen, Philomena Pullikotil, Nicoletta Senese, Manfredi Tesauro, Davide Lauro, Carmine Cardillo, Michael J Quon
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 96 Issue 5 Pg. E782-92 (May 2011) ISSN: 1945-7197 [Electronic] United States
• PMID: 21346065 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Necrosis Factor-alpha
• Nitric Oxide
• Hesperidin
• Nitric Oxide Synthase Type III
• Oncogene Protein v-akt
• Adenylate Kinase

Topics

• Adenylate Kinase (metabolism)
• Animals
• Cattle
• Cell Adhesion (drug effects)
• Cells, Cultured
• Cross-Over Studies
• Double-Blind Method
• Endothelial Cells (drug effects, metabolism)
• Endothelium, Vascular (physiology)
• Female
• Hesperidin (pharmacology)
• Humans
• Inflammation (metabolism)
• Male
• Metabolic Syndrome (metabolism)
• Middle Aged
• Monocytes (drug effects)
• Nitric Oxide (biosynthesis)
• Nitric Oxide Synthase Type III (metabolism)
• Oncogene Protein v-akt (metabolism)
• Signal Transduction (drug effects)
• Stimulation, Chemical
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, pharmacology)
• Vasodilation (physiology)