GLUT4 Determines Vascular Responses in Hypertension

GLUT4 决定高血压的血管反应

• 批准号: 8016113
• 负责人: Frank C Brosius
• 金额: $ 33.16万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8016113
• 关键词: Affect; Agonist; Animal Model; Animals; Arteries; Blood Pressure; Blood Vessels; Calcium; Caveolae; Cell Differentiation process; Cells; Characteristics; Chronic; Coupled; DOCA; Data; Development; G Protein-Coupled Receptor Signaling; GLUT4 gene; Glucose; Human; Hypertension; Insulin; Insulin Resistance; Intervention; Investigation; Knockout Mice; Lead; Mediating; Membrane Microdomains; Mus; Pathway interactions; Patients; Phenotype; Play; Research Personnel; Rho-associated kinase; Rodent; Role; Serotonin; Signal Pathway; Signal Transduction; Signaling Molecule; Smooth Muscle Myocytes; Smooth Muscle Myosins; Sodium Chloride; Study Section; Testing; Tissues; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Vascular Smooth Muscle; caveolin 1; glucose metabolism; glucose transport; glucose uptake; knockout animal; morphometry; myosin phosphatase; prevent; protective effect; protein transport; receptor; response; rho; serotonin receptor; sugar

DESCRIPTION (provided by applicant): GLUT4, the so-called insulin-responsive transporter, is expressed in vascular smooth muscle cells (VSMCs) and participates in basal glucose uptake in VSMCs in an insulin-independent manner. VSMC GLUT4 expression is decreased in many animal models of hypertension, several of which are not associated with generalized insulin resistance. We have found that decreased GLUT4 in VSMCs results in altered vascular contractility and cell signaling. Specifically, in transgenic and knockout animals, reduction of GLUT4 enhances vascular reactivity whereas increased GLUT4 expression prevents hypertension-induced increases in reactivity. Thus, our general hypothesis is that reduction in VSMC GLUT4 expression leads to phenotypic changes in arteries that are characteristic of hypertension. We have found that reduction in GLUT4 expression causes reduced myosin light chain phosphatase activity and that this is likely mediated by Rho kinase. These effects are of potential significance since altered Rho-kinase activity plays a pivotal role in the development of vascular abnormalities in hypertensive animal models and humans. Thus we hypothesize that reduction in VSMC GLUT4 expression leads to enhanced RhoA/Rho-kinase activity which is responsible for phenotypic changes in arteries in hypertension. Our data also suggest that GLUT4 is functionally coupled with certain VSMC agonist receptors such as 5-HT2 receptors. Myosin phosphatase inhibition by 5-HT is augmented by specific blockade of GLUT4-mediated glucose uptake; 5-HT2 receptors and GLUT4 are associated with caveolae and lipid rafts in VSMCs. Thus, we hypothesize that GLUT4 interacts with 5-HT2 receptors or G12/13, GEFs and/or other signaling molecules to reduce 5-HT mediated induction of the RhoA/Rho-kinase pathway. In order to test these hypotheses, we will pursue the following three aims, to: 1. Assess the effects of VSMC-specific modulation of GLUT4 expression on blood pressure and other vascular phenotypes in mice with and without DOCA-salt hypertension. 2. Determine the effects of altered VSMC GLUT4 expression on RhoA/Rho kinase pathway, and alternative pathways that mediate calcium sensitization of arterial VSMCs. 3. Determine how GLUT4-dependent effects on vascular smooth muscle myosin phosphatase are mediated via G-protein coupled receptor (GPCR) signaling pathways. LAY SUMMARY: We have found that a protein that transports sugar (glucose) into cells is also involved in preventing abnormalities found in blood vessels from hypertensive animals (and probably humans). We propose studies to determine the mechanisms of these protective effects that could lead to interventions to prevent the vascular damage that occurs in patients with hypertension.

描述（由申请人提供）：GLUT4，所谓的胰岛素反应转运蛋白，在血管平滑肌细胞（VSMC）中表达，并以胰岛素独立的方式参与VSMC中的基础葡萄糖摄取。在许多高血压动物模型中，VSMC GLUT4表达降低，其中一些与广义胰岛素抵抗无关。我们发现，VSMC中GLUT4的降低会导致血管收缩性和细胞信号的改变。具体而言，在转基因和基因敲除动物中，GLUT4的减少可增强血管反应性，而GLUT4表达的增加可防止高血压诱导的反应性增加。因此，我们的一般假设是，VSMC GLUT4表达的降低会导致高血压特征的动脉的表型变化。我们发现，GLUT4表达的降低会导致肌球蛋白轻链磷酸酶活性降低，并且可能是由R​​ho激酶介导的。这些作用具有潜在的意义，因为改变的Rho-激酶活性在高血压动物模型和人类的血管异常发展中起着关键作用。因此，我们假设VSMC GLUT4表达的降低会导致RhoA/Rho-kinase活性增强，这导致了高血压中动脉的表型变化。我们的数据还表明，GLUT4在功能上与某些VSMC激动剂受体（如5-HT2受体）耦合。 5-HT的肌球蛋白磷酸酶抑制作用被特定的GLUT4介导的葡萄糖摄取的特异性阻断增强。 5-HT2受体和GLUT4与VSMC中的小窝和脂质筏有关。因此，我们假设GLUT4与5-HT2受体或G12/13，GEFS和/或其他信号分子相互作用，以降低5-HT介导的RhoA/Rho-kinase途径的诱导。为了检验这些假设，我们将追求以下三个目的：1。评估GLUT4表达对血压和其他具有DOCA-SALT高血压的小鼠中血压和其他血管表型的影响。 2。确定改变的VSMC GLUT4表达对RhoA/Rho激酶途径的影响，以及介导动脉VSMC钙敏化的替代途径。 3。确定如何通过G蛋白偶联受体（GPCR）信号通路介导GLUT4依赖性对血管平滑肌肌球蛋白磷酸酶的影响。 摘要摘要：我们发现，将糖（葡萄糖）转运到细胞中的蛋白质也参与了预防高血压动物（可能是人类）血管中发现异常的异常。我们建议研究确定这些保护作用的机制，这些机制可能导致干预措施，以防止高血压患者发生血管损伤。

项目成果

Sex dimorphic actions of rosiglitazone in generalised peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-deficient mice.

• DOI: 10.1007/s00125-010-1748-2
• 发表时间: 2010-07
• 期刊: DIABETOLOGIA
• 影响因子: 8.2
• 作者: Duan, S. Z.;Usher, M. G.;Foley, E. L.;Milstone, D. S.;Brosius, F. C., III;Mortensen, R. M.
• 通讯作者: Mortensen, R. M.