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Citrus Polyphenol Hesperidin Stimulates Production of Nitric Oxide in Endothelial Cells while Improving Endothelial Function and Reducing Inflammatory Markers in Patients with Metabolic Syndrome

Citrus Polyphenol Hesperidin Stimulates Production of Nitric Oxide in Endothelial Cells while Improving Endothelial Function and Reducing Inflammatory Markers in Patients with Metabolic Syndrome:

Citrus Polyphenol Hesperidin Stimulates Production of Nitric Oxide in Endothelial Cells while Improving Endothelial Function and Reducing Inflammatory Markers in Patients with Metabolic Syndrome

  1. Stefano Rizza*,
  2. Ranganath Muniyappa*,
  3. Micaela Iantorno,
  4. Jeong-a Kim,
  5. Hui Chen,
  6. Philomena Pullikotil,
  7. Nicoletta Senese,
  8. Manfredi Tesauro,
  9. Davide Lauro,
  10. Carmine Cardilloand
  11. Michael J. Quon

-Author Affiliations

  1. Diabetes Unit (R.M., M.I., H.C., P.P., M.J.Q.), National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland 20892; Department of Internal Medicine (S.R., N.S., M.T., D.L.), University of Rome “Tor Vergata”, 00133 Rome, Italy; Department of Internal Medicine (C.C.), Catholic University “Sacro Cuore”, 00168 Rome, Italy; and Department of Medicine (J.K.), Division of Endocrinology, University of Alabama at Birmingham, Birmingham, Alabama 39294
  1. Address all correspondence and requests for reprints to: Michael J. Quon, M.D., Ph.D., Department of Medicine, Division of Endocrinology, Diabetes & Nutrition, University of Maryland at Baltimore, 660 West Redwood Street, Room HH 495, Baltimore, Maryland 21201. E-mail:quonm@medicine.umaryland.edu.

  1. ↵* S.R. and R.M. made equal contributions.

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 H2O2. 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 ± 1.19vs. 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.

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