Caveolin-1 and vascular dysfunction

描述(由申请人提供)： 小窝蛋白-1(Cav-1)存在于多种细胞类型中，包括脂肪细胞、血管内皮细胞和平滑肌细胞，在这些细胞中，它调节酶和受体信号，并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显的关联；然而，它们关联的遗传基础尚未被发现。最近，我们在高血压患者中发现了Cav-1基因变异与胰岛素抵抗(IR)之间的新关联，并发现血管对血管紧张素II的反应发生改变。Cav-1基因敲除(KO)小鼠也表现出IR，血管松弛和血管收缩改变；此外，这些血管异常依赖于内皮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相似发现，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血管功能障碍的主要决定因素，并且Cav-1通过与MR的相互作用调节对生理性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大我们的新的初步调查结果。首先，我们将确定Cav-1基因变异是否是患有胰岛素抵抗的高血压患者体内血管功能障碍表型的决定因素。其次，我们将在体内评估内皮特异的Cav-1 KO小鼠，内皮细胞Cav-1和MR是血管功能的关键调节因子的假设。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，目前的应用开始解决Cav-1作为IR高血压患者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。这一建议的结果可能会改善IR和高血压患者的预防和区别治疗选择。 公共卫生相关性： 小窝蛋白-1是一种与细胞内重要的信号机制相互作用的蛋白质，包括调节血管功能和降低血糖水平以响应胰岛素的能力。最近，我们确定小窝蛋白-1缺乏与胰岛素反应能力(胰岛素抵抗)和血管收缩能力降低有关。该项目将评估小窝蛋白-1基因变异导致高血压和胰岛素抵抗患者血管功能改变的机制。

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.