Role of Oral Microbiota on Vascular Function

糖尿病(DM)和牙周病(PD)是一种复杂的慢性疾病 双向关系。患有帕金森病的人心脏病发作、中风或 严重的心血管并发症。糖尿病患者的帕金森病加重炎症 导致血管疾病(VD)的反应。我们的小组之前已经证明帕金森病会增加冠心病的心脏 糖尿病患者的疾病。一氧化氮(NO)介导的内皮功能障碍是 血管性痴呆的发展。由于缺乏四氢生物蝶呤[BH4，一种用于治疗的辅助因子]，降低了无生物利用度 内皮型一氧化氮合酶[eNOS]，导致eNOS解偶联，增加氧化 糖尿病患者应激/炎症、血管平滑肌松弛受损并参与心血管病变 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受损有关。此外, 核因子(红系衍生-2)样2(NRF2)依赖的抗氧化剂水平降低和增加 活性氧簇(ROS)水平在高血压和血管功能中也起着关键作用。我们 最近报道原代培养的人主动脉内皮细胞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，我们在体内的啮齿动物研究表明，慢性 牙周多菌感染[齿密螺旋体(TD)和核梭杆菌(FN)，模型 [帕金森病患者]可降低感染者阻力血管中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 帕金森病和糖尿病导致的内皮功能障碍是完全未知的。我们的中心假设是BH4 调节NO介导的血管功能，与糖尿病或帕金森病相比，糖尿病帕金森病患者的血管功能严重受损 独自一人。具体目的是：1：确定高血糖是否加重帕金森病所致的损害 BH4/NOS和PHAECs中的NO下游信号转导。2：调查内源性BH4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，以及NO介导的血管松弛。拟议中的研究将是第一次确定 牙周病原体在2型糖尿病动物模型NO介导的血管功能中的作用。这些概述中的研究 AIMS具有翻译相关性，因为它有可能确定新的治疗方法；PD/T2 DM诱导的选择 痴呆症。

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.