title: Polybacterial Periodontal Pathogens Alter Vascular and Gut BH4/nNOS/NRF2-Phase II Enzyme Expression.
abstract: Periodontal disease is a highly prevalent chronic inflammatory disease and is associated with complex microbial infection in the subgingival cavity. Recently, American Heart Association supported a century old association between periodontal disease and atherosclerotic vascular disease. We have recently shown that polybacterial periodontal infection led to aortic atherosclerosis and modulation of lipid profiles; however the underlying mechanism(s) has not been yet demonstrated. Altered nitric oxide (NO) synthesis and tetrahydrobiopterin (BH4), a cofactor for nitric oxide synthases (NOS) has long been shown to be associated with vascular dysfunction and gastrointestinal motility disorders. We sought to examine the mechanism of periodontal infection leading to altered vascular and gastrointestinal smooth muscle relaxation, focusing on the BH4/nNOS pathways. In addition, we also have investigated how the antioxidant system (NRF2-Phase II enzyme expression) in vascular and GI specimens is altered by oral infection. Eight week old male ApoEnull mice were either sham-infected or infected orally for 16 weeks with a mixture of major periodontal bacteria Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia to induce experimental periodontitis. Serum, vascular (mesenteric), stomach, and colon specimens were collected at the end of periodontal pathogen infection. Bacterial infection induced significant (p<0.05) reductions in the levels of BH4,in ratio of BH4:BH2+B and also in nitric oxide levels compared to sham-infected controls. In addition, we identified a significant (p<0.05) reduction in eNOS dimerization, nNOS dimerization and protein expression of BH4 biosynthesis enzymes; GCH-1, DHFR and NRF2 & Phase II enzymes in infected mice versus controls in both mesenteric artery and colon tissues. However, we found no differences in nNOS/BH4 protein expression in stomach tissues of infected and sham-infected mice. This suggests that a polybacterial infection can cause significant changes in the vascular and colonic BH4/nNOS/NRF2 pathways which might lead to impaired vascular relaxation and colonic motility.
authors.affiliation: Department of Physiology, Meharry Medical College, Nashville, TN, United States of America; School of Dentistry, Meharry Medical College, Nashville, TN, United States of America.
authors.forename: Pandu
authors.initials: P
authors.lastname: Gangula
authors.affiliation: Department of Physiology, Meharry Medical College, Nashville, TN, United States of America.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Ravella
authors.affiliation: Department of Periodontology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Sasanka
authors.initials: S
authors.lastname: Chukkapalli
authors.affiliation: Department of Periodontology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rivera
authors.affiliation: Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: Department of Cardiovascular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Ashley
authors.initials: A
authors.lastname: Hale
authors.affiliation: Department of Cardiovascular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Keith
authors.initials: K
authors.lastname: Channon
authors.affiliation: School of Dentistry, Meharry Medical College, Nashville, TN, United States of America.
authors.forename: Janet
authors.initials: J
authors.lastname: Southerland
authors.affiliation: Department of Periodontology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America; Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Lakshmyya
authors.initials: L
authors.lastname: Kesavalu
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D016866:Bacteroidaceae Infections / Q000378:metabolism / Q000382:microbiology*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000382:microbiology*; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D010510:Periodontal Diseases / Q000378:metabolism / Q000382:microbiology*; D016966:Porphyromonas gingivalis; D048373:Treponema denticola
chemical_list: D001057:Apolipoproteins E; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D001708:Biopterins; D052248:Nitric Oxide Synthase Type I; C003402:sapropterin