Role of Oral Microbiota on Vascular Function

糖尿病（DM）和牙周病（PD）是复杂的慢性疾病， 双向关系。PD患者发生心脏病发作、中风或中风的风险是正常人的两到三倍。 严重的心血管并发症。糖尿病患者的PD导致炎症加重 导致血管疾病（VD）的反应。我们的研究小组先前已经表明，PD增加冠心病， 糖尿病患者的疾病。一氧化氮（NO）介导的内皮功能障碍是内皮细胞凋亡的初始步骤。 VD的发展。由于缺乏四氢生物蝶呤[BH 4，一种辅助因子， 内皮型一氧化氮合酶（eNOS）]，导致eNOS解偶联，增加氧化 应激/炎症，血管平滑肌松弛受损，并导致糖尿病患者的CV病理 糖尿病患者和啮齿动物模型。我们以前的研究表明，慢性牙周感染， 降低循环BH 4和NO水平，这种降低与受损的免疫信号传导相关。此外，本发明还提供了一种方法， 核因子（红细胞衍生的-2）样2（Nrf 2）依赖性抗氧化剂水平降低， 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，牙龈卟啉单胞菌感染的原代人主动脉内皮细胞（pHAECs (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， 减少Nrf 2/eNOS和BH 4生物合成。此外，我们的体内啮齿动物研究表明， 多细菌牙周感染[Pg，齿垢密螺旋体（Td）和具核梭杆菌（Fn），模型 PD的人]减少感染的阻力血管中Nrf 2/BH 4/nNOS的蛋白表达。 小鼠然而，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是完全未知的。我们的核心假设是BH 4 调节NO介导的血管功能，与糖尿病或PD相比， 一个人具体目的是：1.确定高血糖（HG）是否加重PD引起的损害 在pHAECs中BH 4/NOS和NO下游信号传导中的作用。2：研究内源性BH 4是否增加 生物合成抑制PD/T2 DM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。拟议中的研究将是第一个确定 牙周病原体在T2 DM动物模型中NO介导的血管功能中的作用。这些研究中概述的 目的具有转化相关性，因为它有可能确定新的治疗方法; PD/T2 DM诱导的选择 性病

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.