Atherogenic Mechanisms Associated with Hyperhomocysteinemia

与高同型半胱氨酸血症相关的动脉粥样硬化机制

• 批准号: 8316243
• 负责人: Hong Wang
• 金额: $ 38.76万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316243
• 关键词: Accounting; Adhesions; Age; Air; Anabolism; Animal Model; Apolipoprotein A-I; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Blood Cells; Bone Marrow Transplantation; Cardiovascular Diseases; Carotid Arteries; Cell Adhesion Molecules; Cells; Cholesterol Esters; Data; Diabetes Mellitus; Diet; Disease; Endothelial Cells; Endothelium; Etiology; Experimental Models; Funding; Genetic; Grant; High Density Lipoproteins; High Prevalence; Homocysteine; Homocystine; Human; Hyperhomocysteinemia; Immigration; Immunohistochemistry; In Vitro; Inflammatory; Injury; Kidney Diseases; Laboratories; Lead; Link; Lipids; Manuscripts; Methionine; Microcirculation; Microscopy; Modeling; Molecular; Mus; Pathogenesis; Peripheral; Physiological; Postmenopause; Publishing; Reporting; Risk Factors; Role; Signal Pathway; Smoking; Sorting - Cell Movement; System; Technology; Testing; Tissues; Triglycerides; Vascular Diseases; Vascular remodeling; Woman; acetyl-LDL; atherogenesis; cell injury; hypercholesterolemia; in vivo; insight; intravital microscopy; migration; molecular marker; monocyte; mouse model; neointima formation; prevent; public health relevance; repaired; uptake

DESCRIPTION (provided by applicant): The overall objective of this competitive renewal application is to determine the molecular mechanisms responsible for Hyperhomocysteinemia (HHcy)-accelerated atherosclerosis. Major discoveries in the previous grant period include; 1) HHcy impairs endothelial function in severe HHcy CBS-/- mice by inhibiting eNOS expression and PKC activation, 2) HHcy inhibits post injury endothelial repair and lead to increase vascular remodeling in severe HHcy, 3) HHcy inhibits HDL biosynthesis via apo-AI inhibition in human and mouse CVD, 4) HHcy accelerates spontaneous atherosclerosis in CBS-/-/apoE-/- mice, 5) HHcy increased vessel wall content of cholesteryl ester (CE) and triglyceride (TG) contents and promoted MC uptake of Acetyl-LDL, 6) HHcy promoted inflammatory MC subset differentiation in hCBStg/mCBS-/-/apoE-/-. Collectively, these findings implicate HHcy in the etiology of inflammatory vascular diseases. The hypothesis to be tested in this proposal is that HHcy accelerates atherosclerosis by activating endothelium, promoting vessel wall inflammatory MC differentiation and increasing MC trans-endothelium migration. This project will study this hypothesis utilizing three linked specific aims. In Aim 1, we will examine the effects and mechanism of HHcy on endothelium activation and monocyte trans-endothelium migration using cultured primary endothelial and splenic cells in static condition or under physiological relevant flow. In Aim 2, we will study the role of HHcy on vessel wall MC origin and its relevance to atherogenesis using bone marrow transplantation from GFP mice into our newly developed HHcy mouse (CBS-/?/-). In Aim 3, we will study the effect of homocysteine-lowering on preventing MC trans-endothelium migration into the vessel wall and on reducing spontaneous atherosclerotic lesion formation. MC rolling/adhesion on EC will be examined in cremaster microcirculation model using intravital microscopy technology. We believe that completion of the specific Aims should Completion of the specific aims of this proposal may provide important insights into the role of Hcy in CVD, and identify the mechanistic links between HHcy and atherosclerosis. PUBLIC HEALTH RELEVANCE: Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases (CVD). It has been suggested that HHcy accounts for the higher prevalence of CVD in renal disease, diabetes, ageing and in postmenopausal women that is not explained by traditional risk factors. However, the underlying mechanism is largely unknown and the role of homocysteine (Hcy)-induced vessel wall lipid accumulation has not been studies. We have demonstrated profound atherogenic effects of HHcy in disease mouse models established in our laboratory. We have recently reported that HHcy accelerates atherosclerosis, and increases inflammatory monocyte subsets in the peripheral tissues. In this proposal, we will use three connected Aims to examine the role and mechanisms of HHcy induced endothelial activation and monocyte-endothelium interaction. Aim 1 will examine the effects and mechanism of HHcy on endothelium activation and monocyte trans-endothelium migration using cultured primary endothelial and splenic cells in static condition or under physiological relevant flow. Aim 2 will study the role of HHcy on vessel wall MC origin and its relevance to atherogenesis using bone marrow transplantation from GFP mice into our newly developed HHcy mouse line (CBS/LRLR-/- mice). Aim 3 will study the effects of homocysteine-lowering on preventing MC trans-endothelium migration into the vessel wall and on reducing spontaneous atherosclerotic lesion formation.

描述（由申请人提供）：这种竞争性更新应用的总体目的是确定负责超体系血症（HHCY）促进动脉粥样硬化的分子机制。上一个赠款期间的主要发现包括： 1) HHcy impairs endothelial function in severe HHcy CBS-/- mice by inhibiting eNOS expression and PKC activation, 2) HHcy inhibits post injury endothelial repair and lead to increase vascular remodeling in severe HHcy, 3) HHcy inhibits HDL biosynthesis via apo-AI inhibition in human and mouse CVD, 4) HHcy accelerates spontaneous CBS - / - /APOE-/ - 小鼠的动脉粥样硬化，5）HHCY增加了胆固醇酯（CE）和甘油三酸酯（TG）含量（TG）含量的血管壁含量，并促进了乙酰基LDL的MC吸收HHCY，HHCY促进了HCBSTG/MCBSTG//APOE的HHCY促进炎症MC子集分化。总的来说，这些发现暗示了HHCY在炎症血管疾病的病因中。在该提案中要检验的假设是，HHCY通过激活内皮，促进血管壁炎症MC分化并增加MC跨内皮迁移来加速动脉粥样硬化。该项目将利用三个链接的特定目的研究这一假设。在AIM 1中，我们将使用在静态条件下或生理相关的流动下，使用培养的原代内皮细胞和脾细胞来检查HHCY对内皮激活和单核细胞跨内皮迁移的影响和机制。在AIM 2中，我们将研究HHCY在血管壁MC起源上的作用及其与动脉粥样硬化的相关性，使用GFP小鼠的骨髓移植到我们新开发的HHCY小鼠（CBS - /？/ - ）中。在AIM 3中，我们将研究降低同型半胱氨酸对防止MC跨内皮细胞迁移到血管壁的影响，并减少自发性动脉粥样硬化病变的形成。 MC滚动/EC上的粘附将在Cremaster微循环模型中使用浸润显微镜技术检查。我们认为，具体目的的完成应完成本提案的具体目的，可以为HCY在CVD中的作用提供重要的见解，并确定HHCY与动脉粥样硬化之间的机械联系。 公共卫生相关性：高脑结膜血症（HHCY）是心血管疾病（CVD）的独立危险因素。有人提出，HHCY在肾脏疾病，糖尿病，衰老和绝经后妇女中的CVD患病率较高，而传统危险因素没有解释。但是，潜在的机制在很大程度上是未知的，同型半胱氨酸（HCY）诱导的血管壁脂质积累的作用尚未研究。我们已经证明了HHCY在我们实验室中建立的疾病小鼠模型中的深刻的动脉粥样硬化作用。我们最近报告说，HHCY加速了动脉粥样硬化，并增加了周围组织中的炎症单核细胞亚群。在此提案中，我们将使用三个相关的目的来检查HHCY诱导的内皮激活和单核细胞 - 内皮相互作用的作用和机制。 AIM 1将使用静态条件或生理相关流动的培养的原代内皮细胞和脾细胞来检查HHCY对内皮激活和单核细胞跨性皮层迁移的影响和机制。 AIM 2将研究HHCY对血管壁MC起源的作用及其与动脉粥样硬化的相关性，使用GFP小鼠的骨髓移植到我们新开发的HHCY小鼠系（CBS/LRLR-/ - 小鼠）中。 AIM 3将研究降低同型半胱氨酸对防止MC跨性皮细胞迁移到血管壁的影响，并减少自发性动脉粥样硬化病变的形成。