Local delivery of nitric oxide prevents endothelial dysfunction in periodontitis. (February 2023)

• Record Type: Journal Article
• Authors: Fernandes, Daniel; Khambata, Rayomand S.; Massimo, Gianmichele; Ruivo, Ernesto; Gee, Lorna C.; Foster, Julie; Goddard, Alison; Curtis, Mike; Barnes, Michael R.; Wade, William G.; Godec, Thomas; Orlandi, Marco; D'Aiuto, Francesco; Ahluwalia, Amrita
• Is Part Of: Pharmacological research. Volume 188(2023)
• Publication Date: 2023-02
• Subjects: Nitrate -- Nitric oxide -- Endothelial dysfunction -- Periodontitis -- Xanthine oxidoreductase; ABC Alveolar bone crest -- ACh Acetylcholine -- CEJ Cemento-enamel junction -- CVD Cardiovascular Disease -- DEA-NO Diethylamine-NONOate -- DPI Diphenyliodonium -- eNOS endothelial nitric oxide synthase -- FMD Flow mediated dilation -- IL Interleukin -- IκB Inhibitor of nuclear factor kappa-light-chain-enhancer of activated B cells -- iNOS Inducible nitric oxide synthase -- KCl Potassium Chloride -- KNO3 Potassium Nitrate -- L-NAME NG-nitro-l-arginine methyl ester -- NADH Nicotinamide adenine dinucleotide -- NADPH β-Nicotinamide adenine dinucleotide 2′-phosphate -- NFκB Nuclear factor kappa-light-chain-enhancer of activated B cells -- NGS Next generation sequencing -- NO Nitric Oxide -- NO3- Nitrate -- NO2- Nitrite -- OTUs Operational Taxonomic Units -- TNFα Tumour necrosis factorα -- XDH Xanthine dehydrogenase -- XOR Xanthine oxidoreductase; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106616
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Aims: Increased cardiovascular disease risk underlies elevated rates of mortality in individuals with periodontitis. A key characteristic of those with increased cardiovascular risk is endothelial dysfunction, a phenomenon synonymous with deficiencies of bioavailable nitric oxide (NO), and prominently expressed in patients with periodontitis. Also, inorganic nitrate can be reduced to NO in vivo to restore NO levels, leading us to hypothesise that its use may be beneficial in reducing periodontitis-associated endothelial dysfunction. Herein we sought to determine whether inorganic nitrate improves endothelial function in the setting of periodontitis and if so to determine the mechanisms underpinning any responses seen. Methods and results: Periodontitis was induced in mice by placement of a ligature for 14 days around the second molar. Treatment in vivo with potassium nitrate, either prior to or following establishment of experimental periodontitis, attenuated endothelial dysfunction, as determined by assessment of acetylcholine-induced relaxation of aortic rings, compared to control (potassium chloride treatment). These beneficial effects were associated with a suppression of vascular wall inflammatory pathways (assessed by quantitative-PCR), increases in the anti-inflammatory cytokine interleukin (IL)-10 and reduced tissue oxidative stress due to attenuation of xanthine oxidoreductase-dependent superoxide generation. In patients with periodontitis, plasma nitrite levels were not associated with endothelial function indicating dysfunction. Conclusion: Our results suggest that inorganic nitrate protects against, and can partially reverse pre-existing, periodontitis-induced endothelial dysfunction through restoration of nitrite and thus NO levels. This research highlights the potential of dietary nitrate as adjunct therapy to target the associated negative cardiovascular outcomes in patients with periodontitis. Graphical Abstract: ga1