HDL and Vascular Injury in Type 2 Diabetes

描述(申请人提供)：在患有2型糖尿病的人类中，心血管(CV)发病率和死亡率增加。糖尿病患者血管成形术后再狭窄的发生率也高于非糖尿病患者。脂蛋白代谢的改变可能导致2型糖尿病患者心血管风险增加和血管重塑。2型糖尿病被认为降低了高密度脂蛋白及其主要蛋白成分载脂蛋白A-I的抗动脉粥样硬化作用。越来越多的注意力集中在新的药物疗法上，这种疗法可以特别提高动脉粥样硬化风险患者的高密度脂蛋白胆固醇。在这一应用中，我们讨论了基于载脂蛋白A-I的结构特征而设计的新型多肽D-4F。给血脂异常的啮齿动物服用D-4F可提高其抗氧化活性，改善高密度脂蛋白的质量，并刺激具有高胆固醇摄取能力的小颗粒高密度脂蛋白的形成。肥胖的Zucker(OZ)大鼠具有高血糖、胰岛素抵抗和血脂异常，通常被用作2型糖尿病的模型。与正常血糖对照组相比，球囊损伤的OZ大鼠颈动脉内膜病变形成显著增加。这种反应与血浆高密度脂蛋白降低、甘油三酯和血糖升高密切相关。推测高密度脂蛋白的血管保护特性将限制OZ大鼠动脉对球囊扩张损伤的过度增殖反应。这可以通过降低致动脉粥样硬化脂蛋白和/或甘油三酯的血浆浓度来实现。进一步推测，D-4F具有抗炎和改善血糖控制的作用，其机制与提高高密度脂蛋白的质量/功能有关。因此，我们建议检验新的载脂蛋白A-I模拟多肽D-4F减少糖尿病OZ大鼠对腔内损伤的夸大反应的普遍假设。这些假说将通过三个目标得到验证，这三个目标将评估D-4F是否：1)通过增加其抗氧化能力和逆转胆固醇的转运来改善高密度脂蛋白的质量/功能；2)抑制OZ大鼠球囊损伤的动脉中促炎症介质的表达；以及3)通过激活过氧化物体增殖物激活的受体-伽马信号通路来改善糖尿病OZ大鼠的血糖控制。这项拟议的研究将确立载脂蛋白A-I模拟肽的疗效，这是一类用于治疗血脂异常的新型药物，特别是在糖尿病的情况下，并将为开发新的治疗方法提供理论基础，这些新方法适用于动脉粥样硬化的高危人群。

DESCRIPTION (provided by applicant): Cardiovascular (CV) morbidity and mortality are increased in humans with type 2 diabetes. Restenosis after angioplasty also occurs more frequently in diabetic patients than in nondiabetics. The altered metabolism of lipoproteins may contribute to increased CV risk and vascular remodeling in type 2 diabetics. Type 2 diabetes is thought to reduce anti-atherogenic effects of HDL and its principal protein component apolipoprotein (apo) A-I. Increasing attention is focusing on new pharmacotherapies that specifically elevate HDL cholesterol in patients at risk for atherosclerosis. In this application, we discuss the novel peptide D-4F whose design is based on structural features of apo A-I. Administration of D-4F to dyslipidemic rodents improves the quality of HDL by increasing its antioxidant activity and stimulates the formation of small HDL particles with high cholesterol uptake capacity. The obese Zucker (OZ) rat is hyperglycemic, insulin resistant and dyslipidemic and is commonly used as a model for type 2 diabetes. Intimal lesion formation is significantly increased in balloon injured carotid arteries of OZ rats compared to normoglycemic controls. This response correlated strongly with reduced plasma HDL and an increase in Tg and glucose. It is hypothesized that vasoprotective properties of HDL will limit the hyperproliferative response to balloon inflation injury in arteries of OZ rats. This may be achieved by reducing plasma concentrations of atherogenic lipoproteins and/or Tg. It is further hypothesized that D-4F exerts anti-inflammatory effects and improves glycemic control by mechanisms related to the improvement in HDL quality/function. Accordingly, we propose to test the general hypothesis that the novel apo A-I mimetic peptide D-4F reduces the exaggerated response to endoluminal injury in diabetic OZ rats. These hypotheses will be tested by 3 aims that will assess whether D-4F: 1) improves HDL quality/function by increasing its anti-oxidant capacity and reverse cholesterol transport in OZ rats; 2) inhibits the expression of proinflammatory mediators in balloon injured arteries of OZ rats; and 3) improves glycemic control in diabetic OZ rats via activation of peroxisome proliferator activated receptor-gamma signaling pathways. The proposed studies will establish the efficacy of apo A-I mimetic peptides, a novel class of drugs for the management of dyslipidemia, particularly in the context of diabetes, and will provide the rationale for the development of new treatment modalities in humans at high risk for atherosclerosis.