Impact of dyslipidemia on endothelial biomechanics

血脂异常对内皮生物力学的影响

基本信息

批准号：
10201709
负责人：
Irena Levitan
金额：
$ 56.85万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-04 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201709
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

项目摘要

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：人们越来越认识到内皮生物力学在多种内皮功能中发挥着关键作用。我们的研究重点是氧化脂质对内皮生物力学的调节，我们证明氧化脂质可以诱导显着的内皮硬化。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变化的贡献内皮功能障碍的机制。在本次赠款的当前资助期内，我们提供了对血脂异常引起的主动脉内皮细胞 (EC) 硬化的重要机制见解显示它主要依赖于 CD36 清道夫受体和 RhoA/ROCK 级联的激活。我们也发现 oxLDL/血脂异常和促动脉粥样硬化血流紊乱 (DF) 环境具有协同作用体外和体内诱导 EC 硬化的作用。在当前的提案中，我们将这些研究扩展到解决三个新目标：在目标1中，我们重点进一步阐明oxLDL诱导EC的机制硬化。首先（目标 1A），我们将确定 CD36 在 EC 硬化中的作用是否是提供路径 oxLDL 内化，随后将氧化脂质掺入膜中，或者是否 CD36 需要诱导信号级联反应，从而导致 EC 硬化。我们还将确定已知与 CD36 结合的脂肪酸对 EC 硬度的影响。在目标的第二部分（1B）中，我们将研究 CD36 介导的 oxLDL 摄取和 RhoA 激活之间的机制联系级联，根据我们的初步数据，我们建议通过 RhoA 与抑制性调节剂 GDI-1。在目标 2 中，我们重点关注 oxLDL/DF 诱导的 EC 硬化在破坏内皮屏障和内皮-单核细胞粘附（目标 2B）。首先（目标 2A），我们是提议深入研究 oxLDL 和 DF 对激活 RhoA/ROCK 级联并区分 RhoA 依赖性 EC 硬化与 RhoA 依赖性 EC 硬化的贡献 EC 屏障破坏导致细胞凋亡。在目标的第二部分（2B）中，我们研究了通过区分 EC 硬化的影响，oxLDL 诱导单核细胞粘附中的 EC 硬化与 oxLDL 诱导的炎症 NFkB 级联激活和 NFkB 表达增加相比内皮粘附分子。在目标 3 中，这些研究被扩展以研究血脂异常引起的体内内皮硬化及其对动脉粥样硬化形成的贡献病变。这一目标将通过使用两种内皮特异性 CD36 缺陷小鼠模型来实现，即 Ti2e- 驱动模型，这是从出生起就缺乏 CD36 的模型和 VEcad 驱动的诱导模型。两种型号都将在两种主要的小鼠血脂异常模型 ApoE-/- 和 LDLR-/- 的背景下进行了测试。综合起来，这些新研究有望为我们对内皮细胞的理解提供重要的新见解血脂异常条件下的生物力学特性，特别是促动脉粥样硬化的血流动力学环境。

项目成果

期刊论文数量（71）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

LDL induces cholesterol loading and inhibits endothelial proliferation and angiogenesis in Matrigels: correlation with impaired angiogenesis during wound healing.

LDL 诱导胆固醇负荷并抑制基质胶中的内皮增殖和血管生成：与伤口愈合过程中血管生成受损的相关性。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Bogachkov, Yedida Y;Chen, Lin;Le Master, Elizabeth;Fancher, Ibra S;Zhao, Yan;Aguilar, Victor;Oh, Myung;Wary, Kishore K;DiPietro, Luisa A;Levitan, Irena
通讯作者：
Levitan, Irena

Control of adipogenesis by ezrin, radixin and moesin-dependent biomechanics remodeling.

通过埃兹蛋白、根蛋白和模蛋白依赖的生物力学重塑控制脂肪生成。

DOI：
发表时间：
2013-02-01
期刊：
影响因子：
2.4
作者：
Titushkin, Igor;Sun, Shan;Paul, Amit;Cho, Michael
通讯作者：
Cho, Michael

Identification of novel cholesterol-binding regions in Kir2 channels.

Kir2 通道中新型胆固醇结合区的鉴定。

DOI：
发表时间：
2013-10-25
期刊：
影响因子：
0
作者：
Rosenhouse;Noskov, Sergei;Durdagi, Serdar;Logothetis, Diomedes E;Levitan, Irena
通讯作者：
Levitan, Irena

Silencing of Kir2 channels by caveolin-1: cross-talk with cholesterol.

Caveolin-1 对 Kir2 通道的沉默：与胆固醇的串扰。

DOI：
发表时间：
2014-09-15
期刊：
影响因子：
0
作者：
Han, Huazhi;Rosenhouse;Gnanasambandam, Radhakrishnan;Epshtein, Yulia;Chen, Zhenlong;Sachs, Frederick;Minshall, Richard D;Levitan, Irena
通讯作者：
Levitan, Irena

Interplay Between Lipid Modulators of Kir2 Channels: Cholesterol and PIP2.

Kir2 通道脂质调节剂之间的相互作用：胆固醇和 PIP2。