HDL and Vascular Injury in Type 2 Diabetes

描述（由申请人提供）：2型糖尿病患者心血管（CV）发病率和死亡率增加。血管成形术后再狭窄在糖尿病患者中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构。2型糖尿病被认为可以降低高密度脂蛋白及其主要蛋白质成分载脂蛋白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治疗上，这些药物可以专门提高动脉粥样硬化危险患者的高密度脂蛋白胆固醇。在这个应用中，我们讨论了新的肽D-4F，其设计是基于载脂蛋白A-I的结构特征。给血脂异常的啮齿动物服用D-4F，通过增加HDL的抗氧化活性和刺激形成具有高胆固醇摄取能力的小HDL颗粒，从而改善HDL的质量。肥胖的Zucker （OZ）大鼠患有高血糖、胰岛素抵抗和血脂异常，通常被用作2型糖尿病的模型。与血糖正常对照组相比，球囊损伤的OZ大鼠颈动脉内膜病变形成明显增加。这种反应与血浆高密度脂蛋白降低、Tg和葡萄糖升高密切相关。假设HDL的血管保护特性将限制OZ大鼠动脉球囊膨胀损伤的超增殖反应。这可以通过降低致动脉粥样硬化脂蛋白和/或Tg的血浆浓度来实现。进一步假设D-4F通过改善HDL质量/功能的相关机制发挥抗炎作用并改善血糖控制。因此，我们提出验证新型载脂蛋白A-I模拟肽D-4F减轻糖尿病OZ大鼠对腔内损伤的过度反应的一般假设。这些假设将通过3个目标进行测试，以评估D-4F是否通过增加其抗氧化能力和逆转胆固醇运输来改善高密度脂蛋白的质量/功能；2)抑制球囊损伤大鼠动脉促炎介质的表达；3)通过激活过氧化物酶体增殖体激活受体- γ信号通路改善糖尿病OZ大鼠的血糖控制。拟议的研究将确定载脂蛋白a - i模拟肽的功效，这是一类用于治疗血脂异常的新型药物，特别是在糖尿病的背景下，并将为开发新的治疗方法提供理论依据，用于动脉粥样硬化高风险人群。

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.