Vascular Dysfunction in Myocardial Ischemia and Metabolic Syndrome

项目概要/摘要 尽管有强有力的证据表明代谢综合征（MetS）与心血管疾病风险增加有关， 尽管心血管疾病（CVD）的发病率增加，但这种风险增加的机制仍不清楚。特别是肥胖、高血压和 糖尿病（代谢综合征的所有组成部分）在该人群中被报告为心脏事件的主要风险因素 是导致死亡的主要原因尽管异常心血管疾病的分子机制 在MetS条件下的体外和啮齿动物模型中研究了它们的功能， 心脏侧支血管的形成在很大程度上是未知的。缺乏证据和延伸， 对这些原则的大型动物和患者进行实验。这种认识是一个必要的先决条件， 人类的应用。 我们将在雄性完整的约克郡猪中用高脂肪喂养诱导具有胰岛素抵抗的MetS， 重现了MetS患者中存在的许多代谢、分子和微循环异常。我们 先前的研究和初步数据表明，猪糖尿病模型与患者的疾病非常相似， 并导致减少心肌和血管再生，我们将在本建议中使用该模型。为了 为了调节血糖水平，我们将用西格列汀和卡格列净治疗猪，并将结果与 精益饮食控制。在本提案中，我们将重点关注SGLT 1抑制对侧支循环的影响。 发育和代谢，分子和微循环异常存在于明显的患者， 糖尿病和代谢综合征。我们的重点是侧支依赖性心肌细胞的功能变化， 灌注、血管密度和微血管功能以及参与改变的关键分子事件。 侧支形成过程。 我们将使用机械的方法来了解分子相互作用的途径和网络和功能 这有助于阐明糖尿病血管生成受损的分子基础。我们已公布的和初步的 数据表明，在己糖胺生物合成途径（HBP）中，柠檬酸 酸循环（CAC）、胰岛素信号传导和蛋白质O-GlcNAc化。 建议的综合方法将导致识别关键途径，分子靶点， 在促血管生成治疗和基于细胞的再生和组织工程的策略，临床重要性 这一建议是显而易见的。2型糖尿病和代谢综合征的大型动物模型的使用是一种有效的方法。 项目的强大方面。

Project Summary/Abstract Despite robust evidence that metabolic syndrome (MetS) is associated with an increased risk of cardiovascular disease (CVD), the mechanism of this increased risk remains obscure. In particular, obesity, hypertension, and diabetes (all components of MetS) have been reported in this population as primary risk factors for cardiac events with the leading cause of mortality. Although the molecular mechanisms underlying abnormal cardiovascular function have been investigated in in-vitro and rodent models under MetS conditions, their exact role in the formation of cardiac collateral vessels is largely unknown. There is a lack of evidence and extension in experiments with large animals and patients of these principles. This awareness is an essential prerequisite for their human application. We will induce MetS with insulin resistance in male intact Yorkshire pigs with high fat feeding a model that recreates many of the metabolic, molecular, and microcirculatory abnormalities present in MetS patients. Our prior studies and preliminary data show that porcine models of diabetes closely resemble the disease in patients and lead to diminish myocardial and vascular regeneration and we will use the model in this proposal. In order to adjust the blood glucose level, we will treat pigs with sitagliptin and canagliflozin and compare the answer to lean diet controls. In this proposal we will concentrate on the effects of SGLT1 inhibition on collateral development and the metabolic, molecular, and microcirculatory abnormalities present in patients with overt diabetes and metabolic syndrome. Our focus is on functional changes in collateral dependent myocardial perfusion, vascular density, and microvascular function together with key molecular events involved in the altered collateral formation process in vivo. We will use mechanistic approach to understand molecular interactions in pathways and networks and functional attributes to unravel the molecular base of impaired angiogenesis in diabetes. Our published and preliminary data suggests for involvement and functional interactions in the hexosamine biosynthetic pathway (HBP), citric acid cycle (CAC), insulin signaling, and protein O-GlcNAcylation. The proposed integrated approach will result in the identification of crucial pathways, molecular targets, and strategies in pro-angiogenic therapy and cell-based regeneration and tissue engineering, the clinical importance of this proposal is evident. The use of a large animal model with type 2 diabetes and metabolic syndrome is a strong aspect of the project.