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）是复杂的慢性疾病，其发病机制已明确 双向关系。帕金森病患者患心脏病、中风或其他疾病的风险是帕金森病患者的两到三倍 严重的心血管并发症。糖尿病患者的帕金森病会加剧炎症 导致血管疾病（VD）的反应。我们的研究小组之前已经表明，PD会增加冠心病的发生 糖尿病患者的疾病。一氧化氮（NO）介导的内皮功能障碍是这一过程的第一步。 VD的发展。由于缺乏四氢生物蝶呤 [BH4（一种辅助因子），NO 生物利用度降低 内皮一氧化氮合酶 (eNOS)]，导致 eNOS 解偶联，增加氧化 压力/炎症、血管平滑肌松弛受损并导致糖尿病患者的心血管病变 糖尿病患者和啮齿动物模型。我们之前的研究表明，慢性牙周感染 循环 BH4 和 NO 水平降低，这种降低与免疫信号传导受损相关。此外， 核因子（红细胞衍生 2）样 2 (Nrf2) 依赖性抗氧化剂水平降低，并增加 活性氧（ROS）水平在高血压和血管功能中也发挥着关键作用。我们 最近报道，原代人主动脉内皮细胞（pHAEC）感染牙龈卟啉单胞菌 （Pg，一种主要的牙周病原体），表现出细胞活力降低，促炎细胞因子升高， Nrf2/eNOS 和 BH4 生物合成减少。此外，我们的体内啮齿动物研究表明，慢性 多菌牙周感染 [Pg、齿垢密螺旋体 (Td) 和具核梭杆菌 (Fn)，模型 [人类PD的作用]降低感染者抵抗血管中Nrf2/BH4/nNOS的蛋白表达 老鼠。然而，导致炎症和氧化应激加重的具体机制 PD和糖尿病导致内皮功能障碍的情况尚不清楚。我们的中心假设是 BH4 调节一氧化氮介导的血管功能，与糖尿病或帕金森病相比，糖尿病帕金森病患者的血管功能受到极大损害 独自的。具体目标是，1：确定高血糖 (HG) 是否会加重帕金森病引起的损伤 pHAEC 中的 BH4/NOS 和 NO 下游信号传导。 2：调查内源性BH4是否增加 生物合成抑制 PD/T2DM 诱导的炎症、氧化应激并恢复 eNOS 活性、NO 合成和NO介导的血管舒张。拟议的研究将首先确定 T2DM 动物模型中牙周病原体对 NO 介导的血管功能的影响。这些中概述的研究 目标具有转化相关性，因为它有可能确定新的治疗方法； PD/T2DM 诱发的选择 VD。