Does Diabetic Hyperglycemia Regulate Atherosclerosis Progression and Regression?

糖尿病高血糖是否调节动脉粥样硬化的进展和消退？

• 批准号: 8397520
• 负责人: Robert Raffai
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397520
• 关键词: Address; Age-Months; Alleles; Amputation; Apolipoprotein E; Apoptosis; Applications Grants; Arteries; Atherosclerosis; Blood; Blood Glucose; Blood Vessels; Blood flow; Brain; Cardiovascular Diseases; Cells; Cessation of life; Cholesterol; Clinical; Clinical Treatment; Collagen; Complication; Diabetes Mellitus; Diabetic mouse; Dialysis procedure; Diet; Disabled Persons; Doctor of Philosophy; Dyslipidemias; Excision; Fatty acid glycerol esters; Foam Cells; Frequencies; Future; Genetically Engineered Mouse; Goals; Healthcare; High Density Lipoproteins; Hyperglycemia; Individual; Inflammation; Inflammatory; Insulin; Investigational Therapies; Ischemia; Kidney; Leg; Limb structure; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mediating; Modeling; Mus; Myocardial Infarction; Operative Surgical Procedures; Pain; Peripheral; Peripheral arterial disease; Planet Mars; Plasma; Principal Investigator; Proteins; Reporting; Research Design; Research Project Grants; Research Project Summaries; Resistance; Resolution; Risk; Risk Factors; Role; Series; Stroke; Testing; Therapeutic; Veterans; artery occlusion; blood lipid; diabetic; experience; feeding; foot; gene repair; hypercholesterolemia; improved; macrophage; monocyte; mouse model; non-diabetic; novel strategies; premature; recombinase; research study; response; therapeutic target; treatment strategy; vascular inflammation

Summary of the research project proposed by Dr. Robert L. Raffai, PhD: Diabetes is associated with a 2- to 4-fold increase in atherosclerosis-related cardiovascular disease including peripheral arterial disease (PAD). Despite this association, little is known about the mechanisms by which diabetic hyperglycemia can accelerate atherosclerosis and complication of PAD that include limb loss and premature death. Moreover, whether hyperglycemia can impair the regression of atherosclerosis is not known. Unfortunately, studies of existing mouse models of atherosclerosis were often marred by the recently recognized effect by which hyperglycemia increases plasma cholesterol levels in diabetic mice. Studies in which hyperglycemia was found to accelerate atherosclerosis also reported increased plasma cholesterol in diabetic mice. Moreover, the lack of suitable mouse models of atherosclerosis regression have hampered studies designed to address the effects of diabetic hyperglycemia on atherosclerosis regression, a promising clinical treatment strategy for cardiovascular disease. We propose to overcome these limitations by studying our newly developed mouse model of spontaneous and reversible dyslipidemia and atherosclerosis called hypomorphic apolipoprotein E mice deficient in the low density lipoprotein receptor (Apoeh/hLdlr-/-Mx1-Cre mice). When fed a low-fat chow diet, these mice, while moderately dyslipidemic, are resistant to further hyperglycemia-induced hypercholesterolemia. Moreover, they develop occlusive peripheral atherosclerosis by 12 to 14 months of age, predisposing to critical limb ischemia and premature death while on a chow diet. Remarkably, their dyslipidemia can be permanently lowered by conditional gene repair of the hypomorphic Apoe allele mediated by inducible Cre activation, which results in atherosclerosis regression within 2 weeks. In Aim 1, we will study hyperglycemic and normoglycemic Apoeh/hLdlr-/-Mx1-Cre mice to assess the extent and frequency of occlusive peripheral atherosclerosis and symptomatic forms of PAD in 12 month old mice. We will also test the hypothesis that in the absence of added dyslipidemia, hyperglycemia enhances systemic inflammation and the pro-inflammatory state of vascular cells in peripheral arteries. We will then test the hypothesis that enhanced vascular inflammation augments monocyte recruitment in peripheral arteries, and that hyperglycemia raises intracellular free cholesterol levels, thereby promoting the unfolded protein response and premature apoptosis of macrophage foam cells. Lastly, we will test the hypothesis that high density lipoproteins isolated from hyperglycemic Apoeh/hLdlr-/-Mx1-Cre mice will display a reduced ability to promote lipid elimination and suppress inflammation, and that low density lipoproteins will have opposite effects. The rapid reversal of dyslipidemia and atherosclerosis in Apoeh/hLdlr-/-Mx1-Cre mice provides a powerful new approach to address mechanisms associated with atherosclerosis regression. Thus, in Aim 2, we will test the hypothesis that hyperglycemia impairs transcriptional reprogramming of vascular cells and thereby the removal of arterial lipid, the egress of macrophages and the accumulation of collagen in response to lipid lowering. Next, we will explore the utility of therapeutic insulin treatment to enhance atherosclerosis regression in hyperglycemic Apoeh/hLdlr-/-Mx1-Cre mice. Our long-term goals are to identify mechanisms that could serve as therapeutic targets to delay the progression and accelerate the regression of atherosclerosis as treatments for PAD in diabetic individuals.

罗伯特·L.博士提出的研究项目摘要。Raffai博士： 糖尿病与动脉粥样硬化相关的心血管疾病增加2- 4倍相关，包括 外周动脉疾病（PAD）。尽管存在这种联系，但人们对这种联系的机制知之甚少。 糖尿病性高血糖可加速动脉粥样硬化和PAD并发症，包括肢体丧失， 过早死亡此外，尚不清楚高血糖是否会损害动脉粥样硬化的消退。 不幸的是，对现有的动脉粥样硬化小鼠模型的研究经常受到最近 在糖尿病小鼠中，高血糖症通过其增加血浆胆固醇水平的公认作用。研究 发现高血糖会加速动脉粥样硬化， 糖尿病小鼠此外，缺乏合适的动脉粥样硬化消退的小鼠模型阻碍了 旨在解决糖尿病高血糖对动脉粥样硬化消退的影响的研究， 心血管疾病的临床治疗策略。 我们建议通过研究我们新开发的自发和自发性的小鼠模型来克服这些局限性。 可逆性血脂异常和动脉粥样硬化称为低形态载脂蛋白E缺乏小鼠在低 密度脂蛋白受体（Apoeh/hLdlr-/-Mx 1-Cre小鼠）。当喂食低脂食物时，这些小鼠， 中度血脂异常，对进一步的高血糖诱导的高胆固醇血症具有抗性。而且他们 在12至14个月大时发生闭塞性外周动脉粥样硬化，易患严重肢体缺血 以及在节食时过早死亡。值得注意的是，他们的血脂异常可以永久降低， 通过诱导型Cre激活介导的亚型Apoe等位基因的条件性基因修复， 2周内动脉粥样硬化消退。 在目的1中，我们将研究高血糖和血糖正常的Apoeh/hLdlr-/-Mx 1-Cre小鼠，以评估其程度和 12月龄小鼠中闭塞性外周动脉粥样硬化和PAD症状形式的频率。我们将 还检验了这样一个假设，即在没有额外血脂异常的情况下，高血糖会增强全身性 炎症和外周动脉中血管细胞的促炎状态。然后我们将测试 增强的血管炎症增加外周动脉中单核细胞募集的假说， 高血糖会提高细胞内游离胆固醇水平，从而促进未折叠蛋白质反应， 以及巨噬泡沫细胞的过早凋亡。最后，我们将检验高密度 从高血糖Apoeh/hLdlr-/-Mx 1-Cre小鼠分离的脂蛋白将显示降低的促进 低密度脂蛋白具有相反的作用。 Apoeh/hLdlr-/-Mx 1-Cre小鼠中血脂异常和动脉粥样硬化的快速逆转提供了一个强有力的新的 方法来解决与动脉粥样硬化消退相关的机制。因此，在目标2中，我们将测试 假设高血糖损害血管细胞的转录重编程，从而去除 动脉脂质，巨噬细胞的流出和胶原蛋白的积累，以响应脂质降低。 接下来，我们将探讨治疗性胰岛素治疗在增强动脉粥样硬化消退中的效用。 高血糖Apoeh/hLdlr-/-Mx 1-Cre小鼠 我们的长期目标是确定可以作为治疗靶点的机制，以延迟 进展和加速动脉粥样硬化的消退作为糖尿病个体中PAD的治疗。

项目成果

Apolipoprotein E enhances microRNA-146a in monocytes and macrophages to suppress nuclear factor-κB-driven inflammation and atherosclerosis.

• DOI: 10.1161/circresaha.117.305844
• 发表时间: 2015-06-19
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Li K;Ching D;Luk FS;Raffai RL
• 通讯作者: Raffai RL

ApoE suppresses atherosclerosis by reducing lipid accumulation in circulating monocytes and the expression of inflammatory molecules on monocytes and vascular endothelium.

• DOI: 10.1161/atvbaha.111.238964
• 发表时间: 2012-02
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Gaudreault N;Kumar N;Posada JM;Stephens KB;Reyes de Mochel NS;Eberlé D;Olivas VR;Kim RY;Harms MJ;Johnson S;Messina LM;Rapp JH;Raffai RL
• 通讯作者: Raffai RL