Insulin Resistance, Vascular Stiffness, and Hypertension

描述（由申请人提供）：纵向研究表明，动脉硬度可以预测高血压的发生，但因果关系尚未得到证实。我们已经在胰岛素抵抗的啮齿动物模型中证明，主动脉硬化发生在高血压发展之前的早期。此外，我们还记录了主动脉壁中基质调节和成骨转录因子、核心结合因子α 1 （Cbfa1）的表达增加。我们假设胰岛素抵抗环境导致血管组织中Cbfa1的不适当表达，导致与血管纤维化和主动脉僵硬相关的一组基因的转录。在Specific Aim 1中，我们将使用遗传和饮食诱导的胰岛素抵抗/高胰岛素血症模型来确定对Cbfa1表达和活性的影响。噻唑烷二酮治疗将用于提高胰岛素敏感性，而调节血管紧张素和一氧化氮活性信号的药物将用于阐明对主动脉Cbfa1表达的影响。在Specific Aim 2中，我们将使用一种新型血管平滑肌特异性Cbfa1转基因小鼠进一步探索Cbfa1与血管刚度之间的关系。主动脉基因表达和平滑肌细胞生长模式将与离体材料刚度测量相关。此外，我们将建立在血管平滑肌中表达显性阴性Cbfa1的新小鼠模型，并测试Cbfa1在胰岛素抵抗诱导的血管僵硬中的重要作用。最后，在Specific Aim 3中，我们将确定Cbfa1过表达对体内动脉僵硬和高血压发展的影响。将测试Cbfa1活性的药理学和遗传学操作对血管僵硬和血压的后续影响。这些特定的目的将研究一种新的机制，可能是胰岛素抵抗背景下血管僵硬的基础。此外，该模型将使我们有机会确定动脉僵硬度和血压升高的时间关系。最后，直接抑制Cbfa1活性将测试靶向血管僵硬是否有利于抑制高血压的发展。

DESCRIPTION (provided by applicant): Longitudinal studies indicate that arterial stiffness can predict incident hypertension but a causal relationship has yet to be demonstrated. We have demonstrated in a rodent model of insulin resistance that aortic stiffness occurs at an early age before the development of hypertension. In addition, we have documented increased expression of the matrix-regulatory and osteogenic transcription factor, core binding factor alpha1 (Cbfa1) in the aortic wall. We hypothesize that the insulin resistant milieu results in inappropriate expression of Cbfa1 in vascular tissue, leading to transcription of a panel of genes associated with vascular fibrosis and aortic stiffness. In Specific Aim 1, we will use both genetic and diet-induced models of insulin resistance/hyperinsulinemia to determine effects upon Cbfa1 expression and activity. Thiazolidinedione treatment will be used to enhance insulin sensitivity while pharmacological agents to modulate angiotensin and nitric oxide activity signaling will be used to elucidate the effects upon aortic Cbfa1 expression. In Specific Aim 2, we will explore further the relationship between Cbfa1 and vascular stiffness using a novel vascular smooth muscle-specific Cbfa1 transgenic mouse. Aortic gene expression and smooth muscle cell growth patterns will be correlated to ex vivo measures of material stiffness. In addition, we will produce a new mouse model that expresses a dominant-negative Cbfa1 in vascular smooth muscle and test the essential role of Cbfa1 in insulin resistance-induced vascular stiffness. Finally, in Specific Aim 3, we will determine the effects of Cbfa1 overexpression on arterial stiffness in vivo and on development of hypertension. Pharmacological and genetic manipulations of Cbfa1 activity will be tested for subsequent effects upon vascular stiffness and blood pressure. These specific aims will investigate a novel mechanism that may underlie vascular stiffness in the setting of insulin resistance. Moreover, this model will give us the opportunity to determine the temporal relationship of arterial stiffness and elevations in blood pressure. Finally, direct inhibition of Cbfa1 activity will test whether targeting vascular stiffness will have benefit in inhibiting development of hypertension. PUBLIC HEALTH RELEVANCE: We have observed increased levels of Cbfa1, a gene related to extracellular matrix and calcification, in the aorta of animal models of vascular stiffness. We propose to use a combination of material testing and imaging modalities to clarify the underlying mechanisms of how this gene can regulate vascular stiffness as well as predispose to the development of hypertension.