Impact of dyslipidemia on endothelial biomechanics

血脂异常对内皮生物力学的影响

• 批准号: 9789917
• 负责人: Irena Levitan
• 金额: $ 57.93万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-04 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789917
• 关键词: 7-ketocholesterol; Address; Adhesions; Apolipoprotein E; Apoptosis; Arterial Fatty Streak; Arteries; Atherosclerosis; Atomic Force Microscopy; Binding; Biomechanics; Birth; Blood Vessels; CD36 gene; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion Molecules; Cell physiology; Cessation of life; Chronic; Coronary heart disease; Data; Descending aorta; Development; Disease; Dissociation; Docking; Dyslipidemias; Endothelial Cells; Endothelium; Environment; Event; Exposure to; Fatty Acids; Fluorescence Resonance Energy Transfer; Functional disorder; Funding; Genetic; Goals; Grant; In Vitro; Induction of Apoptosis; Inflammation; Inflammatory; Lead; Lesion; Ligands; Link; Lipids; Low-Density Lipoproteins; Mediating; Membrane; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Outcome; Oxides; Pathway interactions; Patients; Phenotype; Phospholipids; Physiological; Plasma; Play; Prevention; Process; Property; Receptor Activation; Regulation; Resistance; Risk Factors; Role; Route; Signal Transduction; Site; Site-Directed Mutagenesis; Specificity; Testing; Woman; aortic arch; athero susceptible; atheroprotective; base; comparative; cytokine; endothelial dysfunction; gain of function; hemodynamics; in vivo; insight; loss of function; men; monocyte; mortality; mouse model; novel; oxidized lipid; oxidized low density lipoprotein; promoter; protective effect; recruit; scavenger receptor; uptake

Abstract: Endothelial biomechanics is increasingly recognized to play a key role in multiple endothelial functions. Our studies focus on regulation of endothelial biomechanics by oxidized lipids, which we showed to induce significant endothelial stiffening. Our long term goal is to elucidate the mechanisms responsible for dyslipidemia-induced changes in endothelial biomechanics and to determine the contribution of these mechanisms to endothelial dysfunction. During the current funding period of this grant, we provided significant mechanistic insights into dyslipidemia-induced stiffening of aortic endothelial cells (EC) showing that it critically depends on CD36 scavenger receptor and activation of RhoA/ROCK cascade. We also discovered that oxLDL/dyslipidemia and pro-atherogenic disturbed flow (DF) environment have a synergistic effect in inducing EC stiffening in vitro and in vivo. In the current proposal, we extend these studies to address three new goals: In Aim 1, we focus on elucidating further the mechanism of oxLDL-induced EC stiffening. First (aim 1A), we will determine whether the role of CD36 in EC stiffening is to provide the route for oxLDL internalization with subsequent incorporation of oxidized lipids into the membrane or whether CD36 is required to induce a signaling cascade that leads to EC stiffening. We will also determine the impact of fatty acids known to bind to CD36 on EC stiffness. In the second part of the aim (1B), we will investigate the mechanistic link between CD36 mediated oxLDL uptake and activation of the RhoA cascade, which based on our preliminary data, we propose to be mediated by the dissociation of RhoA from the inhibitory regulator GDI-1. In Aim 2, we focus on the role of oxLDL/DF-induced EC stiffening in the disruption of the endothelial barrier and endothelial-monocyte adhesion (aim 2B). First (aim 2A), we are proposing to investigate in depth the synergistic impact of oxLDL and DF on the activation of the RhoA/ROCK cascade and to discriminate between the contributions of RhoA-dependent EC stiffening vs. apoptosis in the disruption of the EC barrier. In the second part of the aim (2B), we investigate the role of oxLDL-induced EC stiffening in monocyte adhesion by discriminating between the impacts of EC stiffening vs. oxLDL-induced activation of the inflammatory NFkB cascade and increase in the expression of endothelial adhesion molecules. In Aim 3, these studies are extended to investigate the mechanism of dyslipidemia-induced endothelial stiffening in vivo and its contribution to the formation of atherosclerotic lesions. This goal will be achieved using two models of endothelial-specific CD36-deficient mice, a Ti2e- driven model, which is CD36-deficient from birth and VEcad-driven inducible model. Both models will be tested on the backgrounds of two major models of mouse dyslipidemia, ApoE-/- and LDLR-/-. Taken together, these new studies are expected to provide significant new insights into our understanding of endothelial biomechanical properties under dyslipidemic conditions particularly in pro-atherogenic hemodynamic environment.

抽象的： 内皮生物力学越来越多地被认为在多种内皮功能中起关键作用。我们的 研究的重点是通过氧化脂质调节内皮生物力学的调节，我们表明是为了诱导的。 明显的内皮僵硬。我们的长期目标是阐明负责的机制 血脂异常引起的内皮生物力学变化，并确定这些贡献 内皮功能障碍的机制。在本赠款的当前资助期间，我们提供了 对血脂异常引起的主动脉内皮细胞（EC）僵硬的大量机械洞察力显示 它在很大程度上取决于CD36清道夫受体和Rhoa/Rock Cascade的激活。我们也是 发现OxLDL/血脂异常和促动脉粥样不安的流动（DF）环境具有协同作用 在诱导EC僵硬的体外和体内的影响。在当前的建议中，我们将这些研究扩展到 解决三个新目标：在AIM 1中，我们专注于进一步阐明OXLDL诱导的EC的机制 僵硬。首先（AIM 1A），我们将确定CD36在EC僵硬中的作用是否是提供路线 对于随后将氧化脂质掺入膜或是否是否 需要CD36诱导导致EC僵硬的信号传导级联。我们还将确定 已知与CD36结合对EC刚度的脂肪酸的影响。在目标的第二部分（1b），我们将 研究CD36介导的OXLDL吸收和RhoA激活之间的机械联系 基于我们的初步数据，我们建议通过Rhoa解离从 抑制性调节剂GDI-1。在AIM 2中，我们关注OXLDL/DF诱导的EC僵硬的作用 内皮屏障和内皮单细胞粘附的破坏（AIM 2B）。首先（AIM 2A），我们是 提议深入研究OXLDL和DF对激活的协同影响 Rhoa/Rock Cascade，并区分Rhoa依赖性EC僵硬VS的贡献。 EC屏障破坏中的凋亡。在目标的第二部分（2b），我们研究了 通过区分EC僵硬的影响，OXLDL诱导的EC僵硬的单核细胞粘附 与OxLDL诱导的炎症NFKB级联激活的激活和表达的增加 内皮粘附分子。在AIM 3中，对这些研究进行了扩展以研究 血脂异常引起的体内内皮僵硬及其对动脉粥样硬化的形成的贡献 病变。使用两种模型的内皮特异性CD36缺陷小鼠Ti2e-将实现此目标。 驱动的模型，从出生和维卡德驱动的诱导模型中是CD36缺陷。两种型号都是 在两种主要模型的小鼠血脂血症，APOE - / - 和LDLR - / - 的背景下进行了测试。在一起， 这些新研究有望为我们对内皮的理解提供重要的新见解 血脂症状下的生物力学特性，尤其是在促动脉粥样形成的血液动力学中 环境。