Caveolin-1 and vascular dysfunction

Caveolin-1 和血管功能障碍

• 批准号: 8136096
• 负责人: Luminita Pojoga
• 金额: $ 43.61万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136096
• 关键词: Ablation; Address; Adipocytes; Affect; Aldosterone; Angiotensin II; Animal Model; Animals; Blood Glucose; Blood Pressure; Blood Vessels; CAV1 gene; Caveolae; Cell membrane; Cells; Characteristics; Data; Dietary Sodium; Endothelium; Enzymes; Event; Functional disorder; Genetic; Genetic Markers; Genetic Variation; Genotype; Glucose tolerance test; Goals; Haplotypes; Hereditary Disease; Heritability; Hormone Receptor; Human; Hypertension; Individual; Infusion procedures; Insulin; Insulin Resistance; Integral Membrane Protein; Knock-out; Knockout Mice; Laboratories; Lead; Leukocytes; Link; Literature; Mediating; Metformin; Mineralocorticoid Receptor; Modeling; Mus; Pathway interactions; Patients; Phenotype; Physiological; Placebos; Prevention; Prophylactic treatment; Proteins; Receptor Signaling; Renal Blood Flow; Research Proposals; Resistance profile; Role; Signal Transduction; Single Nucleotide Polymorphism; Smooth Muscle; Smooth Muscle Myocytes; Surrogate Markers; Testing; Tissues; Translational Research; Variant; Vascular Endothelial Cell; Vasodilation; base; brachial artery; caveolin 1; cell type; cohort; eplerenone; genetic variant; glucose tolerance; improved; in vivo; insulin sensitivity; kidney vascular structure; knockout animal; molecular marker; mouse model; normotensive; novel; public health relevance; response; salt intake; salt sensitive; trend; vasoconstriction

DESCRIPTION (provided by applicant): Caveolin-1 (cav-1) has been identified in many cell types including adipocytes, vascular endothelial cells and smooth muscle cells - where it modulates enzyme and receptor signaling and is involved in both vascular function and insulin sensitivity. Furthermore, there is a clear association between insulin resistance and hypertension; however, the genetic underpinnings of their association are yet to be discovered. Recently, we identified in hypertensive but not normotensive humans, a novel association between cav-1 gene variants and insulin resistance (IR), as well as an altered vascular response to angiotensin II. Cav-1 knockout (KO) mice also displayed IR, and altered vasorelaxation and vasoconstriction; moreover, these vascular abnormalities were dependent on the presence of the endothelium and on the activation state of the mineralocorticoid receptor (MR). Thus, based on our parallel findings in animals and humans, the central hypothesis for the current proposal is that genetic variation in the cav-1 gene is a major determinant of vascular dysfunction in hypertensive and insulin resistant individuals, and that cav-1 - via its interaction with the MR - modulates endothelial events critical for the physiologic vascular response. The overall goal of the present proposal is to expand on our novel preliminary findings in three ways. First, we will determine whether genetic variation at the cav-1 locus is a determinant of vascular dysfunction phenotypes in vivo in hypertensive humans with IR. Second, we will assess in vivo in endothelium-specific cav-1 KO mice, the hypothesis that endothelial cav-1 and MR are critical modulators of vascular function. Third, we will determine in vivo whether insulin sensitization (by metformin) will affect the vascular dysfunction phenotype in the generalized cav-1 KO model. Thus, the current application begins to address the role of cav-1 as one of the genetic underpinnings of vascular dysfunction in IR hypertensive individuals, and explores mechanisms by which endothelial cav-1 maintains vascular tone. The findings resulting from this proposal could lead to improved prevention and differential treatment options for patients with IR and hypertension. PUBLIC HEALTH RELEVANCE: Caveolin-1 is a protein that interacts with important signaling mechanisms inside the cells, including the ability to regulate blood vessel function and to lower blood sugar levels in response to insulin. Recently we have determined that caveolin-1 deficiency is associated with inability to respond to insulin (insulin resistance) and with reduced contractility of the blood vessels. This project will assess the mechanisms by which genetic variation in caveolin-1 can lead to changes in blood vessel function in individuals with high blood pressure and insulin resistance.

描述（由申请人提供）： Caveolin-1（cav-1）已在许多细胞类型中被鉴定，包括脂肪细胞、血管内皮细胞和平滑肌细胞-在其中它调节酶和受体信号传导并且参与血管功能和胰岛素敏感性。此外，胰岛素抵抗和高血压之间存在明确的关联;然而，其关联的遗传基础尚未被发现。最近，我们在高血压而非血压正常的人群中发现了cav-1基因变异与胰岛素抵抗（IR）以及血管对血管紧张素II反应改变之间的新关联。Cav-1基因敲除（KO）小鼠也显示IR，并改变血管舒张和血管收缩;此外，这些血管异常依赖于内皮细胞的存在和盐皮质激素受体（MR）的激活状态。因此，基于我们在动物和人类中的平行发现，当前提议的中心假设是cav-1基因的遗传变异是高血压和胰岛素抵抗个体中血管功能障碍的主要决定因素，并且cav-1 -通过其与MR的相互作用-调节对生理血管反应至关重要的内皮事件。本提案的总体目标是从三个方面扩展我们新的初步发现。首先，我们将确定是否在cav-1基因座的遗传变异是一个决定因素的血管功能障碍的表型在体内高血压的人与IR。第二，我们将评估在体内内皮特异性cav-1基因敲除小鼠，假设内皮cav-1和MR是血管功能的关键调制器。第三，我们将在体内确定胰岛素增敏（二甲双胍）是否会影响广义cav-1 KO模型中的血管功能障碍表型。因此，本申请开始解决cav-1作为IR高血压个体中血管功能障碍的遗传基础之一的作用，并探索内皮cav-1维持血管张力的机制。这项建议的结果可能会改善IR和高血压患者的预防和差异化治疗选择。 公共卫生相关性： Caveolin-1是一种与细胞内重要信号机制相互作用的蛋白质，包括调节血管功能和响应胰岛素降低血糖水平的能力。最近，我们已经确定小窝蛋白-1缺乏与不能对胰岛素作出反应（胰岛素抵抗）和血管收缩力降低有关。该项目将评估小窝蛋白-1的遗传变异导致高血压和胰岛素抵抗个体血管功能变化的机制。