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）和牙周疾病（PD）是复杂的慢性疾病，已建立 双向关系。患有PD的人的风险是心脏病发作，中风或 严重的心血管并发症。患有糖尿病患者的PD会导致加剧性炎症 导致血管疾病（VD）的反应。我们的小组以前表明PD增加了冠心心 糖尿病患者的疾病。一氧化氮（NO）介导的内皮功能障碍是 VD的发展。由于缺乏四氢无菌蛋白[BH4，辅助因子的辅助因子而没有降低生物利用度 内皮一氧化氮合酶（eNOS）]，导致eNOS解偶联，增加氧化剂 压力/炎症，血管平滑肌松弛受损，并导致糖尿病的CV病理 糖尿病的患者和啮齿动物模型。我们以前的研究表明慢性牙周感染 循环BH4和无水平降低，这种还原与免疫信号受损相关。此外， 核因子水平降低（红细胞来源-2）类似2（NRF2）依赖性抗氧化剂，并增加 活性氧（ROS）的水平在高血压和血管功能中也起关键作用。我们 最近报道说，原发性人主动脉内皮细胞（PHAEC）感染了卟啉念珠菌 （PG，一种主要的牙周病原体），表现出降低的细胞活力，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了慢性 多生细菌牙周感染[PG，Treponema Denticola（TD）和螺杆核核（FN），一种模型 人类的PD]降低了感染的抗药性血管中NRF2/BH4/NNO的蛋白质表达 老鼠。但是，在炎症和氧化应激中导致严重的炎症和氧化应激的特定机制 导致内皮功能障碍的PD和糖尿病是完全未知的。我们的中心假设是BH4 调节NO介导的血管功能，与糖尿病或PD相比 独自的。具体目的是：1：确定高血糖（HG）是否加剧了PD诱导的损害 在BH4/NOS中，没有PHAEC中的下游信号传导。 2：研究内源性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，否 合成，没有介导的血管松弛。拟议的研究将是第一个确定的作用 T2DM动物模型中无介导的血管功能的牙周病原体。这些研究概述了 Aims具有转化相关性，因为它具有识别新颖治疗方法的潜力。 PD/T2DM诱导的选项 vd。