title: 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: BACKGROUND
  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).
  
  
  METHODS
  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.affiliation: Department of Internal Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rizza
authors.forename: Ranganath
authors.initials: R
authors.lastname: Muniyappa
authors.forename: Micaela
authors.initials: M
authors.lastname: Iantorno
authors.forename: Jeong-a
authors.initials: JA
authors.lastname: Kim
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Philomena
authors.initials: P
authors.lastname: Pullikotil
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Senese
authors.forename: Manfredi
authors.initials: M
authors.lastname: Tesauro
authors.forename: Davide
authors.initials: D
authors.lastname: Lauro
authors.forename: Carmine
authors.initials: C
authors.lastname: Cardillo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Quon
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D018592:Cross-Over Studies; D004311:Double-Blind Method; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D006569:Hesperidin / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism*; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology
chemical_list: D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D006569:Hesperidin; D052250:Nitric Oxide Synthase Type III; D051058:Oncogene Protein v-akt; D000263:Adenylate Kinase