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

• 批准号: 10308045
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308045
• 关键词: Animal Model; Arterial Fatty Streak; Atherosclerosis; Bacterial Proteins; Biological Availability; Cell Line; Cells; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; 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; Knowledge; LDL Cholesterol Lipoproteins; Lesion; Lipids; Lipoproteins; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; Oxidoreductase; Patients; Pharmaceutical Preparations; Plasma; Process; Reaction; Residual state; Risk; Risk Factors; Role; SR-B proteins; Serum; Site; Skin; Sterol O-Acyltransferase; Stroke; Surface; Testing; Time; Tissues; Wild Type Mouse; acetyl-LDL; atherogenesis; atheroprotective; cardioprotection; cardiovascular disorder risk; cell type; drug development; macrophage; mortality; mouse model; novel; opacity factor; overtreatment; particle; prevent; small molecule; western diet

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.

虽然高血浆浓度的LDL-C（“坏胆固醇”）与动脉粥样硬化相关， 在心血管疾病（ACVD）中，他汀类药物降低血浆LDL-C并随之降低ACVD。相比之下，高密度 脂蛋白-胆固醇（HDL-C;“好胆固醇”）与ACVD成反比。然而，试图减少 通过血浆HDL-C水平升高的ACVD失败了。新的证据表明，HDL的质量更 比数量更重要，其从巨噬细胞（MΦ）中去除游离胆固醇（FC）的能力， 细胞类型是其最重要的抗动脉粥样硬化作用。这个过程，MΦ-FC流出，启动FC 转移到肠中进行处置-一种抗动脉粥样硬化的过程。奇怪的是，血浆水平非常高的患者 HDL-C水平是ACVD的高风险;潜在的机制尚不清楚，目前没有 以心脏保护方式逆转高HDL-C水平的干预措施。我们假设潜在的 在血浆HDL-C水平非常高的患者中，ACVD的原因是过高的HDL， FC在细胞和脂蛋白之间自由转移。这种状态使FC具有高度生物利用度， 与从动脉壁去除FC相比，富含FC的HDL将FC转移到动脉壁MΦ-一个致动脉粥样硬化的过程。 使用具有潜在高HDL-C水平的ACVD小鼠模型（SR-B1-/-小鼠），我们计划鉴定HDL-FC 生物利用度作为ACVD的驱动因素，并显示用降低HDL的细菌蛋白（血清混浊）治疗 因子），与腺相关病毒一起递送，预防/逆转ACVD。在这个ACVD-HDL轴中，我们 提出以下具体目标： 目的1-比较野生型和SR-B1-/- HDL-[3 H]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，同时鉴定[3 H]FC和[3 H]CE蓄积的组织部位， 以及AAVSOF与AAVGFP对这些动力学和组织分布的影响。 目的2a-为了检验HDL和J774 MΦ之间的FC通量从流出转换为流入的假设， 增加HDL-FC生物利用度，其是HDL颗粒浓度和HDL-FC含量（摩尔%）的函数 FC）。目的2b-与目的1同时，检验HMGCoA还原酶和ACAT活性 通过增加HDL-FC的生物利用度，分别降低和增加MΦ-FC的含量。目标2c- 为了检验HDL-FC生物利用度增加诱导J774 MΦ中泡沫细胞形成的假设。 目的3-检验通过AAVSOF相对于AAVGFP递送降低HDL-FC预防和/或逆转HDL-FC的假设。 SR-B1-/-小鼠的动脉粥样硬化。 这些目标的完成将为研究高血浆HDL-1水平是否会导致高脂血症提供一个令人信服的理论基础。 FC与高HDL-C患者的ACVD相关，●用于开发降低HDL-FC的药物。