RAGE/mDia1, Macrophage Trafficking and Inflammation in Regression of Diabetic Atherosclerosis

总结 心血管疾病（CVD）是糖尿病患者发病和死亡的主要原因。 尽管对脂质和葡萄糖水平进行了积极的管理，但1型和2型糖尿病患者都表现出 与非糖尿病受试者相比，更早发生和更广泛的动脉粥样硬化病变，以及对脂质- 降低策略的有效性显著低于在非糖尿病受试者中观察到的有益效果。 在糖尿病动物中的临床前研究显示， 动脉粥样硬化斑块，以及斑块中巨噬细胞（MCAs）的保留增加。我们将专注于 糖尿病驱动的动脉粥样硬化消退受损机制和MMPs的特殊作用 扰动我们提出的研究是建立在发现移植来自Ldlr-/-的主动脉弓的基础上的。 小鼠转化为糖尿病小鼠，糖尿病小鼠中缺乏DIFF 1或其胞质结构域结合伴侣DIAPH 1， 信号转导，显示显著改善斑块消退，独立于血糖变化 或脂质水平，相比野生型糖尿病小鼠。我们早期的研究表明， 血管壁对高血糖反应的关键成分，RAGE驱动机制 解释了观察到的动脉粥样硬化的加速和进展。在这个应用程序中，使用模型 高血糖症和胰岛素抵抗（IR），我们将测试的假设， 高血糖症和胰岛β细胞/DIAPH 1依赖性机制调节胰岛β细胞的运输（募集和 滞留/淤滞），二尖瓣炎性极化和二尖瓣代谢和氧化应激， 收敛于抑制糖尿病中已形成的动脉粥样硬化斑块的消退。我们将测试小说 在我们的糖尿病动脉粥样硬化消退的鼠模型中， 这些研究将为糖尿病促进胰岛素累积的特定机制提供新的见解 和损害消退，并促进糖尿病动脉粥样硬化的新型治疗药物的开发。

Summary Cardiovascular disease (CVD) represents the major cause of morbidity and mortality in patients with diabetes. Despite aggressive management of levels of lipids and glucose, both types 1 and 2 diabetic patients exhibit earlier onset and more extensive atherosclerotic lesions than non-diabetic subjects, and the response to lipid- lowering strategies is significantly less robust than the beneficial effects noted in non-diabetic subjects. Preclinical studies in diabetic animals have shown accelerated progression and impaired regression of atherosclerotic plaques, as well as increased retention of macrophages (MØs) in plaques. We will focus on diabetes-driven mechanisms linked to impaired atherosclerosis regression and the specific role of MØ perturbation. Our proposed studies are built on the discovery that transplantation of aortic arches from Ldlr-/- mice into diabetic mice deficient in RAGE or its cytoplasmic domain binding partner, DIAPH1, required for RAGE signaling, display significantly improved plaque regression, independent of changes in plasma glucose or lipid levels, compared to wild-type diabetic mice. Our earlier studies demonstrated that activation of RAGE is a critical component of the vessel wall response to hyperglycemia and that RAGE-driven mechanisms accounted for the observed acceleration and progression of atherosclerosis. In this application, using models of hyperglycemia and insulin resistance (IR), we will test the hypothesis that the consequences of hyperglycemia and RAGE/DIAPH1-dependent mechanisms in MØs modulate MØ trafficking (recruitment & retentions/stasis), MØ inflammatory polarization and MØ metabolism and oxidative stress, mechanisms which converge to suppress regression of established atherosclerotic plaques in diabetes. We will test novel pharmacological antagonists of RAGE/DIAPH1 in our murine model of diabetic atherosclerosis regression. These studies will provide novel insights into diabetes specific mechanisms that promote MØ accumulation and impair regression, and foster the development of novel therapeutic adjuncts for diabetic atherosclerosis.