MECHANISMS OF RESISTANCE ARTERY STRUCTURAL REMODELING IN HYPERTENSION

高血压中阻力动脉结构重塑的机制

• 批准号: 8167897
• 负责人: KHALID MATROUGUI
• 金额: $ 16.39万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167897
• 关键词: Adenoviruses; Antioxidants; Arteries; Blood Vessels; Cessation of life; Collagen Type I; Computer Retrieval of Information on Scientific Projects Database; Dominant-Negative Mutation; Down-Regulation; Funding; Grant; Hypertension; I-kappa B Proteins; Infection; Institution; Integrins; Mediating; Mesentery; Mitochondria; Modeling; Molecular; Mus; Myocardial Infarction; NF-kappa B; NFKB Activation Pathway; Oxidative Stress; Pathway interactions; Patients; Research; Research Personnel; Residual state; Resistance; Resources; Risk; Risk Factors; Role; Small Interfering RNA; Source; TNFRSF5 gene; United States National Institutes of Health; Vascular Diseases; acetovanillone; blood pressure regulation; mitoquinone; overexpression; p65; receptor; resistance mechanism

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background and hypothesis: Vascular disease is the major risk factor responsible for myocardial infarction in hypertensive patients. However, the molecular mechanisms that mediate vascular disease in hypertension are poorly understood. Even with the most aggressive treatment available, there is an enormous amount of residual vascular risk responsible for a large number of deaths in the UNITED STATES. Our central hypothesis is that elevated oxidative stress activates NFKB pathway, which leads to avb3-integrin shedding responsible for the increased TGFb1 bio-activity and subsequently the induction of structural wall remodeling in Ang-II-dependent hypertensive mice. We will use mesenteric resistance arteries (MRA) because they are good model reflecting changes in vessels, representative of microvessels and responsible for more than 30% blood pressure control. We have two Specific Aims under this proposal: Overall, our Specific Aim 1 is focused on the role of oxidative stress and NFKB pathways responsible for the increased collagen type 1 content, stiffness, and eutrophic remodeling induction of MRA from Ang-II-dependent hypertensive mice. Subaim 1a: treatment of Ang-II-dependent hypertensive mice apocynin or mitoquinone (MitoQ: is a mitochondria-targeted antioxidant that selectively blocks mitochondrial oxidative stress)", and the use of mice that over-express mitochondrial MnSOD infused with Ang-II to reduce NFKB pathway activation and translocation, avb3-integrin shedding, TGFb1 bioactivity, eutrophic remodeling, collagen type 1 content, and stiffness of MRA from Ang-II-dependent hypertensive mice; Subaim 1b: local down regulation of NFKB pathway by local infection of MRA from ANG II-dependent hypertensive mice with adenovirus-mediated IKB or p50/p65 NFKB subunits-siRNA delivery potentiates or reduces, respectively, avb3-integrin shedding, TGFb1 expression, collagen type 1 content, stiffness and eutrophic remodeling induction; Overall, our Specific Aim 2 is directed to determine the role of avb3-integrin shedding and TGFb1 bio-activity on collagen type 1 content, stiffness, and eutrophic remodeling induction in MRA from Ang-II-dependent hypertensive mice. To accomplish this aim, we will ascertain if: 2a: local down regulation of avb3-integrin by local infection of MRA from ANG II-dependent hypertensive mice with adenovirus-mediated avb3-integrin-siRNA delivery and the use of pharmacological inhibition of avb3-integrin reduce the increased TGFb1 bioactivity, collagen type 1 content, stiffness, and eutrophic remodeling induction of MRA from; 2b: local down regulation of TGFb1 by local infection of MRA from ANG II-dependent hypertensive mice with adenovirus-mediated TGFb1-siRNA delivery, and the use of mice overexpressing dominant negative TGFb1 receptor infused with ANG II reverse the increased collagen type 1 content, stiffness, and eutrophic remodeling induction of MRA.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 背景和假设： 血管疾病是高血压患者发生心肌梗死的主要危险因素。 然而，介导高血压血管疾病的分子机制知之甚少。 即使采用最积极的治疗方法，仍存在巨大的残余血管风险，导致美国大量死亡。 我们的中心假设是，升高的氧化应激激活NF κ B通路，这导致avb 3-整联蛋白脱落负责增加TGF β 1生物活性，随后诱导血管紧张素II依赖性高血压小鼠的结构壁重塑。 我们将使用肠系膜阻力动脉（MRA），因为它们是反映血管变化的良好模型，代表微血管，并负责30%以上的血压控制。 我们在这项建议下有两个具体目标： 总的来说，我们的具体目标1集中在氧化应激和NF κ B通路的作用，这些通路导致Ang-II依赖性高血压小鼠MRA的1型胶原含量增加、硬度和富营养化重塑诱导。 Subaim 1a：夹竹桃素或米托醌治疗Ang-II依赖性高血压小鼠（MitoQ：是一种选择性阻断线粒体氧化应激的靶向MnSOD的抗氧化剂）"，以及使用过表达线粒体MnSOD的小鼠输注Ang-II以减少NF κ B途径活化和易位、avb 3-整联蛋白脱落、TGF β 1生物活性、富营养化重塑、1型胶原含量，Ang-II依赖性高血压小鼠MRA的硬度; Subaim 1b：通过用腺病毒介导的IKB或p50/p65 NF κ B亚单位-siRNA递送局部感染来自ANG II依赖性高血压小鼠的MRA来局部下调NF κ B通路，分别增强或减少avb 3-整合素脱落、TGF β 1表达、1型胶原含量、僵硬和富营养化重塑诱导; 总体而言，我们的具体目标2旨在确定avb 3-整联蛋白脱落和TGF β 1生物活性对Ang-II依赖性高血压小鼠MRA中1型胶原含量、硬度和富营养化重塑诱导的作用。 为了达到这个目标，我们将确定： 2a：通过用腺病毒介导的avb 3-整联蛋白-siRNA递送局部感染来自ANG II依赖性高血压小鼠的MRA来局部下调avb 3-整联蛋白，并使用avb 3-整联蛋白的药理学抑制来降低来自ANG II依赖性高血压小鼠的MRA的增加的TGF β 1生物活性、1型胶原含量、硬度和富营养化重塑诱导; 2b：通过用腺病毒介导的TGF β 1-siRNA递送局部感染来自ANG II依赖性高血压小鼠的MRA来局部下调TGF β 1，以及使用输注ANG II的过表达显性负性TGF β 1受体的小鼠逆转增加的1型胶原含量、硬度和MRA的富营养化重塑诱导。