HDL and Vascular Injury in Type 2 Diabetes

HDL 和 2 型糖尿病的血管损伤

• 批准号: 7342398
• 负责人: C Roger WHITE
• 金额: $ 29.64万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7342398
• 关键词: Angioplasty; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Antioxidants; Apolipoprotein A-I; Apolipoproteins; Apolipoproteins B; Arteries; Atherosclerosis; Attention; Binding; Blood Vessels; Cardiovascular system; Carotid Arteries; Cell Adhesion Molecules; Cell model; Cell surface; Cholesterol; Cholesterol Homeostasis; Class; Coronary Arteriosclerosis; D-4F peptide; Data; Defect; Development; Diabetes Mellitus; Disease; Dyslipidemias; Economic Inflation; Elevation; Enzymes; Extracellular Matrix; Functional disorder; Glucose; High Density Lipoprotein Cholesterol; Human; Hyperglycemia; Inflammatory; Injury; Insulin Resistance; LDL Cholesterol Lipoproteins; Lesion; Lipid Peroxides; Lipids; Lipoproteins; Mediator of activation protein; Menotropins; Metabolism; Modality; Modeling; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidoreductase; PPAR gamma; Paraoxonase 1; Particle Size; Patients; Peptides; Percutaneous Transluminal Coronary Angioplasty; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Property; Proteins; Risk; Rodent; Signal Pathway; Signal Transduction; Stents; System; Testing; Thinking; Triglycerides; Vascular remodeling; Very low density lipoprotein cholesterol; Zucker Rats; aryldialkylphosphatase; base; cardiovascular risk factor; clinically significant; cytokine; design; diabetic; disorder risk; extracellular; glycemic control; hydroxymethylglutarate; implantation; improved; inhibitor/antagonist; injured; leptin receptor; mimetics; mortality; neointima formation; non-diabetic; novel; particle; response; response to injury; restenosis; reverse cholesterol transport; uptake; vascular smooth muscle cell proliferation

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.

描述（由申请方提供）：2型糖尿病患者的心血管（CV）发病率和死亡率增加。糖尿病患者血管成形术后呼吸暂停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CV风险增加和血管重塑。2型糖尿病被认为降低了HDL及其主要蛋白组分载脂蛋白（apo）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，特别是提高高密度脂蛋白胆固醇的患者在动脉粥样硬化的风险。在本申请中，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。给血脂异常的啮齿类动物施用D-4F通过增加其抗氧化活性来改善HDL的质量，并刺激具有高胆固醇摄取能力的小HDL颗粒的形成。肥胖Zucker（OZ）大鼠是高血糖、胰岛素抵抗和血脂异常的，并且通常用作2型糖尿病的模型。与血糖正常的对照组相比，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HDL降低以及Tg和葡萄糖增加密切相关。假设HDL的血管保护特性将限制OZ大鼠动脉中对球囊膨胀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Tg的血浆浓度来实现。进一步假设D-4F通过与HDL质量/功能改善相关的机制发挥抗炎作用并改善血糖控制。因此，我们建议测试的一般假设，即新的载脂蛋白A-I模拟肽D-4F减少夸大的反应，在糖尿病OZ大鼠腔内损伤。这些假设将通过3个目的进行检验，这些目的将评估D-4F是否：1）通过增加OZ大鼠中HDL的抗氧化能力和胆固醇逆向转运来改善HDL质量/功能; 2）抑制OZ大鼠球囊损伤动脉中促炎介质的表达; 3）通过激活过氧化物酶体增殖物激活受体-γ信号通路来改善糖尿病OZ大鼠的血糖控制。拟议的研究将确定载脂蛋白A-I模拟肽的疗效，这是一类新型药物，用于管理血脂异常，特别是在糖尿病的背景下，并将为开发动脉粥样硬化高风险人群的新治疗方式提供理论依据。

项目成果

Vasculoprotective Effects of Apolipoprotein Mimetic Peptides: An Evolving Paradigm In Hdl Therapy (Vascular Disease Prevention, In Press.).

载脂蛋白模拟肽的血管保护作用：HDL疗法中不断发展的范例（预防血管疾病，印刷中）。

• DOI: 10.2174/1567270000906010122
• 发表时间: 2009-01-01
• 期刊: Vascular disease prevention
• 作者: White CR;Datta G;Mochon P;Zhang Z;Kelly O;Curcio C;Parks D;Palgunachari M;Handattu S;Gupta H;Garber DW;Anantharamaiah GM
• 通讯作者: Anantharamaiah GM

The Apolipoprotein E Mimetic Peptide AEM-2 Attenuates Mitochondrial Injury And Apoptosis In Human THP-1 Macrophages.

载脂蛋白 E 模拟肽 AEM-2 可减轻人 THP-1 巨噬细胞的线粒体损伤和细胞凋亡。

• 发表时间: 2018
• 期刊: Current topics in peptide & protein research
• 作者: Giordano-Mooga,Samantha;Datta,Geeta;Wolkowicz,Paul;Garber,DavidW;Palgunachari,Mayakonda;White,CRoger;Anantharamaiah,GM
• 通讯作者: Anantharamaiah,GM

The apoA-I mimetic peptide 4F protects apolipoprotein A-I from oxidative damage.

apoA-I 模拟肽 4F 可保护载脂蛋白 A-I 免受氧化损伤。

• DOI: 10.1016/j.chemphyslip.2019.01.009
• 发表时间: 2019
• 期刊: Chemistry and physics of lipids
• 影响因子: 3.4
• 作者: White,CRoger;Datta,Geeta;Wilson,Landon;Palgunachari,MayakondaN;Anantharamaiah,GM
• 通讯作者: Anantharamaiah,GM