Role of Oral Microbiota on Vascular Function

口腔微生物群对血管功能的作用

• 批准号: 10628184
• 负责人: PANDU R GANGULA
• 金额: $ 14.55万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628184
• 关键词: Anabolism; Animal Model; Antioxidants; Aorta; Attenuated; Biological Availability; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Survival; Chronic; Chronic Disease; Collaborations; Communicable Diseases; Complex; Coronary heart disease; Cyclic GMP; Data; Development; Diabetes Mellitus; Dietary Supplementation; Dimerization; Disease model; Early Diagnosis; Endothelial Cells; Enzymes; Erythroid; Event; Exhibits; Female; Forsythia; Fusobacterium nucleatum; Goals; Gram-Negative Bacteria; Human; Hyperglycemia; Hypertension; Immune signaling; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Laboratories; Measures; Mediating; Modeling; Molecular; Mus; Muscle relaxation phase; Myocardial Infarction; NOS3 gene; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Oral cavity; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Periodontal Diseases; Periodontal Infection; Periodontitis; Persons; Play; Porphyromonas gingivalis; Protein Kinase; Publications; Reactive Oxygen Species; Relaxation; Reporting; Research; Research Personnel; Resistance; Risk; Rodent; Rodent Model; Role; Signal Transduction; Soluble Guanylate Cyclase; Stroke; Supplementation; Testing; Texas; Time; Treponema denticola; Vascular Diseases; Vascular Endothelium; Vascular Smooth Muscle; antioxidant enzyme; cardiovascular risk factor; cofactor; college; cytokine; diabetic; diabetic patient; effective intervention; endothelial dysfunction; enzyme activity; enzyme biosynthesis; experience; improved; in vivo; male; non-diabetic; novel; oral infection; oral microbial community; oxidation; pathogen; periodontopathogen; protein expression; sepiapterin; tetrahydrobiopterin; vascular endothelial dysfunction

Diabetes Mellitus (DM) and periodontal diseases (PD) are complex chronic diseases with an established bidirectional relationship. People with PD have two to three times the risk of having a heart attack, stroke, or serious cardiovascular complications. PD in individuals with diabetes contributes to aggravated inflammatory response leading to vascular disease (VD). Our group has previously shown that PD increases coronary heart disease in diabetic patients. Nitric oxide (NO) mediated endothelial dysfunction is the initial step in the development of VD. Reduced NO bioavailability due to the lack of tetrahydrobiopterin [BH4, a cofactor for endothelial nitric oxide synthase (eNOS)], resulting in eNOS uncoupling, increases oxidative stress/inflammation, impaired vascular smooth muscle relaxation and contributes to CV pathologies in diabetic patients and rodent models of diabetes. Our previous studies demonstrated that chronic periodontal infection reduced circulatory BH4 and NO levels and this reduction correlated with impaired immune signaling. In addition, decreased levels of nuclear factor (erythroid-derived-2)-like 2 (Nrf2)-dependent antioxidants and increased levels of reactive oxygen species (ROS) also play a critical role in hypertension and vascular function. We recently reported that primary human aortic endothelial cells (pHAECs) infected with Porphyromonas gingivalis (Pg, a major periodontal pathogen), exhibited reduced cell viability, elevated pro-inflammatory cytokines, reduced Nrf2/eNOS and BH4 biosynthesis. In addition, our in-vivo rodent studies demonstrate that chronic polybacterial periodontal infection [Pg, Treponema denticola (Td), and Fusobacterium nucleatum (Fn), a model of PD in humans] reduced the protein expression of Nrf2/BH4/nNOS in resistance blood vessels of the infected mice. However, the specific mechanisms that contribute to aggravated inflammation and oxidative stress during PD and diabetes leading to endothelial dysfunction is completely unknown. Our central hypothesis is that BH4 regulates NO-mediated vascular function, which is greatly impaired in diabetic PD compared to diabetes or PD alone. The specific aims are,1: To determine whether hyperglycemia (HG) aggravates PD-induced impairment in BH4/NOS and NO downstream signaling in pHAECs. 2: To investigate whether increased endogenous BH4 biosynthesis suppresses PD/T2DM induced inflammation, oxidative stress and restores eNOS activity, NO synthesis, and NO mediated vascular relaxation. The proposed studies will be the first to determine the role of periodontal pathogens in NO-mediated vascular function in T2DM animal models. The research outlined in these aims has translational relevance, as it has the potential to identify novel treatment; options for PD/T2DM induced VD.

糖尿病（DM）和牙周病（PD）是一种复杂的慢性疾病