Atheroprotection via Reduced Plasma High Density Lipoprotein-Free Cholesterol Bioavailability

通过降低血浆高密度脂蛋白胆固醇生物利用度来预防动脉粥样硬化

基本信息

批准号：
10523525
负责人：
Henry J. Pownall
金额：
$ 40.38万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10523525
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A Animal Model Arterial Fatty Streak Atherosclerosis Bacterial Proteins Biological Availability Cell Line Cells Cholesterol Cholesterol Esters Cholesterol Homeostasis Correlation Studies Data Dependovirus Development Drug or chemical Tissue Distribution Event Excretory function Feces Fibroblasts Foam Cells Goals Hepatic High Density Lipoprotein Cholesterol High Density Lipoproteins Human Intervention Intestines Kinetics Knockout Mice Knowledge LDL Cholesterol Lipoproteins Lesion Lipids Lipoproteins Low-Density Lipoproteins Macrophage Modeling Morbidity - disease rate Myocardial Infarction Oxidoreductase Patients Pharmaceutical Preparations Plasma Process Reaction Residual state Risk Risk Factors Role SR-B proteins Satellite Viruses Serum Site Skin Sterol O-Acyltransferase Stroke Surface Testing Tissues Wild Type Mouse acetyl-LDL atherogenesis atheroprotective cardioprotection cardiovascular disorder risk cell type drug development mortality mouse model novel opacity factor particle prevent small molecule western diet

项目摘要

Although high plasma concentrations of LDL-C (“bad cholesterol”) are associated with atherosclerotic cardiovascular disease (ACVD), statins reduce plasma LDL-C and with it ACVD. In contrast, high density lipoprotein-cholesterol (HDL-C; “good cholesterol”) varies inversely with ACVD. However attempts to reduce ACVD via increased plasma HDL-C levels have failed. New evidence suggests that HDL quality is more important than quantity and that its ability to remove free cholesterol (FC) from macrophages (MΦ), an important cell type in ACVD, is its most important atheroprotective quality. This process, MΦ-FC efflux, initiates the FC transfer to the intestine for disposal—an atheroprotective process. Paradoxically, patients with very high plasma HDL-C levels are at high ACVD risk; the underlying mechanism is unknown, and currently there are no interventions that reverse high HDL-C levels in a cardioprotective way. We hypothesize that the underlying cause of ACVD in patients with very high plasma HDL-C levels is too much HDL that contains high amounts of FC, which transfers freely among cells and lipoproteins. This state makes FC highly bioavailable so that rather than removing FC from the arterial wall, FC-rich HDL transfers FC to arterial-wall MΦ—an atherogenic process. Using a mouse model of ACVD with underlying high HDL-C levels (SR-B1-/- mouse) we plan to identify HDL-FC bioavailability as a driver of ACVD and show that treatment with an HDL-lowering bacterial protein (serum opacity factor), delivered with an adeno-associated virus prevents/reverses ACVD. Within this ACVD-HDL axis, we propose the following specific aims: Aim 1—To compare the plasma clearance kinetics of wild-type and SR-B1-/- HDL-[3H]FC and cholesteryl ester (CE) in wild-type and SR-B1-/- mice, simultaneously identifying the tissue sites of [3H]FC and [3H]CE accretion, and the effects of AAVSOF vs. AAVGFP on these kinetics and tissue distributions. Aim 2a—To test the hypothesis that FC flux between HDL and J774 MΦ switches from efflux to influx with increasing HDL-FC bioavailability, which is a function of HDL particle concentration and HDL-FC content (mol% FC). Aim 2b—Concurrently with Aim 1, to test the hypothesis that HMGCoA reductase and ACAT activities decrease and increase, respectively, MΦ-FC content as effected by increasing HDL-FC bioavailability. Aim 2c— To test the hypothesis that increased HDL-FC bioavailability induces foam cell formation in J774 MΦ. Aim 3—To test the hypothesis that reduction of HDL-FC by AAVSOF vs. AAVGFP delivery prevents and/or reverses atherosclerosis in SR-B1-/- mice. Completion of these aims will provide a compelling rationale ●for studies to determine whether high plasma HDL- FC is associated with ACVD in patients with high HDL-C and ●for the development of drugs that lower HDL-FC.

尽管低密度脂蛋白胆固醇（“坏胆固醇”）血浆浓度高与动脉粥样硬化有关心血管疾病（ACVD）时，他汀类药物会降低血浆 LDL-C 并随之降低 ACVD。脂蛋白胆固醇（HDL-C；“好胆固醇”）与 ACVD 成反比。通过提高血浆 HDL-C 水平的 ACVD 已失败，新证据表明 HDL 质量更高。其从巨噬细胞 (MΦ) 中清除游离胆固醇 (FC) 的能力比数量更重要，这是一种重要的 ACVD 中的细胞类型是其最重要的动脉粥样硬化保护特性，该过程 MΦ-FC 外流启动 FC。转移到肠道进行处理——这是一个动脉粥样硬化保护过程，但血浆浓度非常高的患者。 HDL-C 水平处于高 ACVD 风险；其潜在机制尚不清楚，目前尚无相关证据。我们进行干预，以心脏保护的方式逆转高 HDL-C 水平。血浆 HDL-C 水平非常高的患者发生 ACVD 的原因是 HDL 过多，其中含有大量 FC，在细胞和脂蛋白之间自由转移，这种状态使得FC具有很高的生物利用度，因此更是如此。与从动脉壁去除 FC 相比，富含 FC 的 HDL 将 FC 转移到动脉壁 MΦ——这是一个致动脉粥样硬化的过程。我们计划使用具有高 HDL-C 水平的 ACVD 小鼠模型（SR-B1-/- 小鼠）来识别 HDL-FC 生物利用度作为 ACVD 的驱动因素，并表明用降低 HDL 的细菌蛋白进行治疗（血清混浊）因子），与腺相关病毒一起传递可预防/逆转 ACVD。提出以下具体目标：目标 1 — 比较野生型和 SR-B1-/- HDL-[3H]FC 和胆固醇酯的血浆清除动力学 (CE)在野生型和SR-B1-/-小鼠中，同时识别[3H]FC和[3H]CE积聚的组织位点，以及 AAVSOF 与 AAVGFP 对这些动力学和组织分布的影响。目标 2a — 检验 HDL 和 J774 MΦ 之间的 FC 通量从流出切换到流入的假设增加 HDL-FC 生物利用度，这是 HDL 颗粒浓度和 HDL-FC 含量（mol%）的函数 FC) 目标 2b—与目标 1 同时，检验 HMGCoA 还原酶和 ACAT 活性的假设。通过增加 HDL-FC 生物利用度，分别降低和增加 MΦ-FC 含量，目标 2c— 检验 HDL-FC 生物利用度增加会诱导 J774 MΦ 中泡沫细胞形成的假设。目标 3 — 检验 AAVSOF 与 AAVGFP 递送减少 HDL-FC 可预防和/或逆转的假设 SR-B1-/- 小鼠的动脉粥样硬化。这些目标的完成将为确定高血浆 HDL- 是否存在的研究提供令人信服的理由。 FC 与高 HDL-C 患者的 ACVD 相关，并且用于开发降低 HDL-FC 的药物。