Vascular Dysfunction in Myocardial Ischemia and Metabolic Syndrome

项目摘要/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 疾病(CVD)，这种风险增加的机制仍然不清楚。尤其是肥胖、高血压和 糖尿病(蛋氨酸的所有组成部分)在该人群中已被报告为心脏事件的主要危险因素 是导致死亡的主要原因。尽管心血管异常的分子机制 已在体外和蛋氨酸条件下的啮齿动物模型中研究了它们的功能，它们在 心脏侧支血管的形成在很大程度上是未知的。缺乏证据，缺乏推广性 用大型动物和病人进行这些原理的实验。这种意识是一个必要的先决条件 它们的人类应用程序。 我们将用高脂肪喂养的雄性完整的约克夏猪诱导产生胰岛素抵抗的蛋氨酸。 重现了许多代谢、分子和微循环异常存在于METS患者。我们的 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 并导致心肌和血管再生减少，我们将在本提案中使用该模型。按顺序 为了调整血糖水平，我们将用西格列汀和卡那格列夫秦治疗猪，并将答案与 精益饮食控制。在本提案中，我们将集中讨论SGLT1抑制对侧支循环的影响 临床患者的发展与代谢、分子和微循环异常 糖尿病和代谢综合征。我们的重点是侧支依赖心肌的功能变化 血流灌注、血管密度和微血管功能以及参与改变的关键分子事件 体内侧支形成过程。 我们将使用机械论的方法来理解分子在途径和网络中的相互作用以及功能 有助于揭示糖尿病血管生成受损的分子基础。我们已出版的和初步的 数据表明，柠檬酸参与了氨基己糖生物合成途径(HBP)的参与和功能相互作用 酸循环(CAC)、胰岛素信号转导和蛋白质O-GlcN酰化。 建议的综合方法将导致识别关键途径、分子靶标和 促血管生成治疗、细胞再生和组织工程的策略，临床重要性 这一提议的影响是显而易见的。使用患有2型糖尿病和代谢综合征的大型动物模型是一种 该项目的强势方面。

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.