Loss of BMP receptor II, inflammation, and atherosclerosis

BMP 受体 II 缺失、炎症和动脉粥样硬化

• 批准号: 8507555
• 负责人: Hanjoong Jo
• 金额: $ 33.33万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507555
• 关键词: Adhesions; Affect; Agonist; Antiatherogenic; Antibodies; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Binding; Binding Proteins; Biochemical; Biological Assay; Blood Pressure; Carotid Arteries; Cholesterol; Co-Immunoprecipitations; Coronary artery; Cytoplasmic Tail; Development; Diabetes Mellitus; Diet; Diffuse; Disease; Embryo; Employee Strikes; Endothelial Cells; Event; Family; Fatty acid glycerol esters; Gene Mutation; Goals; Human; Hypertension; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Intercellular adhesion molecule 1; Knock-out; Knockout Mice; Knowledge; LIM Domain Kinase 1; Laboratories; Lesion; Ligation; Measurement; Mediating; Microscopy; Modeling; Molecular Conformation; Mus; NADPH Oxidase; NF-kappa B; Oxidative Stress; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Play; Production; Protein Kinase; Proteins; Proteomics; Reactive Oxygen Species; Regulation; Risk Factors; Role; Scaffolding Protein; Signaling Protein; Site; Small Interfering RNA; Smoking; Staining method; Stains; TNFRSF5 gene; Testing; Trees; Vascular Cell Adhesion Molecule-1; Vascular Diseases; base; blood lipid; bone morphogenetic protein receptor type II; bone morphogenetic protein receptors; bone morphogenic protein; caveolin 1; cytokine; feeding; hypercholesterolemia; in vivo; inflammatory marker; inhibitor/antagonist; insight; loss of function; mRNA Expression; member; monocyte; mouse model; mouse p47; mutant; novel; novel diagnostics; novel therapeutics; prevent; primary pulmonary hypertension; protein expression; pulmonary arterial hypertension; receptor; rho GTP-Binding Proteins; screening; shear stress; vascular inflammation

Atherosclerosis is an inflammatory disease, occurring preferentially in arterial regions associated with disturbed flow while sparing the undisturbed flow regions. We have shown that exposure of endothelial cells (EC) to disturbed flow conditions stimulates production of bone morphogenic protein 4 {BMP4), which induces inflammatory responses in ECs and hypertension in mice. Recently, while studying the mechanism of BMP4 action, we made the surprising paradoxical observation that siRNA-mediated knockdown of the BMP receptor type II (BMPRII), instead of blocking the inflammatory response as we initially hypothesized, induces a striking inflammatory response in EC. We also found that BMPRII expression decreases as the atherosclerotic lesion advances in human coronary arteries. Similar observations were made in a novel model of flow-induced atherosclerosis using a partial ligation of the carotid artery in Apo-E null mice. Our preliminary results further show that BMPRII deficiency dramatically accelerates the development of atherosclerosis in the partially liqated model using BMPRir'ApoE'' mice, while it is significantly blunted in p47phox-deficient ApoE-null mice (P47'^APOE )¿ demonstrating the critical role of BMPRII and NADPH oxidases in the flow-induced atherosclerosis model. We also found that the pro-inflammatory cytokine TNFa decreases BMPRII expression, whereas the cholesterol lowering statins increase it in cultured endothelial cells. These intriguing findings led us to propose that loss of BMPRII may be a central event in lesion initiation and progression at sites of disturbed flow. Defining the underlying mechanisms through which BMPRII is involved in vascular inflammation and atherosclerosis is the specific goal of this application. The pathophysiological importance of BMPRII in vascular inflammation and atherosclerosis is not known. However, genetic mutations of BMPRII are a major cause of familial primary pulmonary hypertension. BMPRII contains a long cytoplasmic tail that binds more than 34 proteins including p50b NFKB, protein kinase Cp and cSrc. Studies suggest that the BMPRII may be a scaffolding protein that keeps the bound proteins inactive until activated by agonist binding, much like how caveolin-1 functions. Here, we will examine the hypothesis that BMPRII expression is downregulated by pro-atherogenic factors including TNFa and upregulated by anti-atherogenic conditions and drugs such as statins. The decrease in BMPRII expression unleashes the signaling proteins that are normally bound to the receptor and kept inactive, resulting in uncontrolled activation of vascular inflammation and subsequent atherosclerosis development in a NADPH oxidase-dependent manner. We will test the hypothesis using ECs and mouse models in four Aims. Aim 1 will define the changes in BMPRII expression in flow-disturbed atherosclerotic lesions in ApoE''' mice fed a high fat diet with or without a partial ligation of the carotid artery. Aim 2 will determine the mechanisms by which statins and TNFa regulate BMPRII expression in ECs and ApoE-null mice. Aim 3 will detennine the mechanisms by which BMPRII knockdown induces inflammation in ECs. Aim 4 will determine the effect of reduced BMPRII expression on inflammation and atherosclerosis using BMPRir''_ApoE-null mice fed a high fat diet. Successful completion of these studies will provide novel insight into understanding the atherogenic mechanisms caused by the loss of BMPRII in the vessel wall, and how atherogenic conditions alter BMPRII levels in endothelial cells. This new knowledge will provide a novel therapeutic and diagnostic target to treat and prevent atherosclerosis.

动脉粥样硬化是一种炎症性疾病，更优选地发生在与分布式流动相关的动脉区域，同时不受干扰的流动区域。我们已经表明，内皮细胞（EC）暴露于流动条件下，刺激了骨形态蛋白4 {BMP4）的产生，从 小鼠EC和高血压的炎症反应。最近，在研究BMP4作用的机制时，我们做出了令人惊讶的矛盾观察，即siRNA介导的BMP受体II型（BMPRII）的敲低，而不是阻止炎症反应，因为我们最初假设的是造成打击 EC中的炎症反应。我们还发现，随着人冠状动脉动脉的动脉粥样硬化病变的发展，BMPRII的表达降低。在新型的流动诱导动脉粥样硬化模型中，使用颈动脉尾动脉中的动脉粥样硬化进行了类似的观察结果。 Our preliminary results further show that BMPRII deficiency dramatically accelerates the development of atherosclerosis in the partially liqated model using BMPRIir'ApoE'' mice, While it is significantly blunted in p47phox-deficient ApoE-null mice (P47'^APOE )¿ demonstrating the critical role of BMPRII and NADPH oxides in the flow-induced 动脉粥样硬化模型。我们还发现，促炎性细胞因子TNFA降低了BMPRII的表达，而降低胆固醇的他汀类药物在培养的内皮细胞中会增加IT。这些有趣的发现使我们 提出，BMPRII的损失可能是受影响流动部位的病变启动和进展的中心事件。定义BMPRII参与血管感染和 动脉粥样硬化是该应用的具体目标。 BMPRII在血管注射和动脉粥样硬化中的病理生理重要性尚不清楚。但是，BMPRII的遗传突变是家族原发性肺动脉高压的主要原因。 BMPRII包含一个长的细胞质尾巴，结合了34多个蛋白质，包括P50B NFKB，蛋白激酶CP和CSRC。研究表明，BMPRII可能是一种脚手架蛋白，它使结合蛋白不活跃直至被激动剂结合激活，就像如何一样 Caveolin-1功能。在这里，我们将研究以下假设：BMPRII的表达被促动脉巨大因素（包括TNFA）下调，并由抗动脉粥样硬化疾病和汀类药物（例如他汀类药物）进行了更新。 BMPRII表达的降低释放了通常结合的信号蛋白 对接收器并保持非活性，导致血管感染的激活和随后的动脉粥样硬化发展以NADPH氧化物依赖性方式发育。我们将在四个目标中使用ECS和小鼠模型检验假设。 AIM 1将定义BMPRII表达的变化 在apoe''小鼠中流动的动脉粥样硬化病变喂养了高脂饮食，有或没有颈动脉的部分连接。 AIM 2将确定他汀类药物和TNFA在ECS和APOE-NULL小鼠中调节BMPRII表达的机制。 AIM 3将阻止BMPRII敲低影响的机制 EC的炎症。 AIM 4将确定使用Bmpriir''_ apoe-null小鼠喂养高脂饮食的BMPRII表达对注射和动脉粥样硬化的影响。这些研究的成功完成将为理解由血管壁中的BMPRII丢失引起的动脉粥样硬化机制以及动脉粥样硬化状况如何改变内皮细胞中的BMPRII水平。这些新知识将为治疗和预防动脉粥样硬化提供新的治疗和诊断靶标。