Atheroregression via Enhanced Reverse Cholesterol Transport

通过增强反向胆固醇转运实现动脉粥样硬化消退

• 批准号: 8819557
• 负责人: Henry J. Pownall
• 金额: $ 58.63万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8819557
• 关键词: Affinity; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein A-I; Apolipoprotein A-II; Apolipoprotein E; Apoproteins; Arterial Fatty Streak; Atherosclerosis; Bacterial Proteins; Base Composition; Binding; Biochemical; Blood flow; Cell Line; Cell model; Cells; Chemicals; Cholesterol; Cholesterol Esters; Complementary therapies; Complex; Data Reporting; Disease; Docking; Dose; Ethers; Etiology; Excision; Future; Goals; Hepatic; Hepatocyte; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; In Vitro; Injection of therapeutic agent; Intestines; Intravenous; LDL Cholesterol Lipoproteins; Learning; Lipids; Lipoprotein (a); Liver; Mediating; Methods; Modality; Modeling; Mus; Myocardial Infarction; Paper; Patients; Pharmaceutical Preparations; Phosphatidylcholine-Sterol O-Acyltransferase; Plasma; Plasma Proteins; Process; Property; Proteins; Public Health; Radio; Reaction; Recombinants; Recruitment Activity; Recycling; Saline; Series; Site; Staging; Streptococcus pyogenes; Stroke; Surface; Testing; Virulence Factors; Water; arterial lesion; base; bile salts; cell type; chemical kinetics; high risk; improved; in vivo; lipid disorder; macrophage; morphometry; mouse model; nonhuman primate; novel; opacity factor; receptor; receptor binding; response; reverse cholesterol transport; success; syndecan; uptake

DESCRIPTION (provided by applicant): Cholesterol, a water insoluble compound, is a major player in the etiology of atherosclerosis. Cholesterol accumulates in plaques in the arterial wall causing obstructed blood flow leading to heart attacks and strokes. Despite the success of the statin class of cholesterol-lowering drugs, which reduce plasma LDL-cholesterol, there remains an unfulfilled need for complementary therapies that promote the removal of cholesterol from atherosclerotic lesions and its transfer to the liver for disposal. We identified a bacterial protein, serum opacity factor (SOF) that at low doses (0.004 mg) rapidly (6 min) and profoundly reduces by half the plasma cholesterol in mice. On the basis of studies with liver cells, we learned that SOF treatment promotes hepatic cholesterol uptake by multiple receptors that bind to a plasma protein, apolipoprotein E. Our plans are to move these discoveries closer to human therapy by completion of several objectives. The first is to show in primary human hepatocytes that the mechanisms for cholesterol removal are as efficient as they are in hepatic cell lines and in mouse liver cells. The second is to determine the contributions of each relevant liver receptor to cholesterol removal. This information would be useful in making choices about the most appropriate co therapy, e.g., a statin. Third, we will show that SOF increases the transfer of cholesterol from macrophages, an important cell type in all stages of atherosclerosis, to the liver for disposal. Lastly, we will show that SOF reverses atherosclerosis in mice. Completion of these objectives would pave the way to future studies in non human primates and ultimately in high risk patients with atherosclerosis. Methods: Radio trace cholesterol uptake and removal by liver cells in response to SOF; use chromatographic methods to show in cells and mice that SOF promotes conversion of macrophage-cholesterol to water-soluble bile salts that enter the intestine for disposal; characterize in mice the changes in response to SOF in the quantity and quality of arterial lesions by chemical analysis and morphometry.

描述（由申请人提供）：胆固醇是一种不溶性化合物，是动脉粥样硬化病因的主要参与者。胆固醇在动脉壁的斑块中积聚，导致血液流动导致心脏病发作和中风。尽管毒药降低血浆LDL-胆固醇的汀类药物类别的成功，但仍需要对互补疗法的需求，这些疗法促进了从动脉粥样硬化病变中去除胆固醇及其转移到肝脏处置的胆固醇。我们确定了一种细菌蛋白，血清不透明度因子（SOF），该因子在低剂量（0.004 mg）中迅速（6分钟），并将小鼠中血浆胆固醇的一半降低一半。根据对肝细胞的研究，我们了解到，SOF治疗促进了与血浆蛋白结合的多种受体促进肝胆固醇的吸收。载脂蛋白E。我们的计划是通过完成几种目标来使这些发现更接近人类治疗。首先是在原代人肝细胞中表明，去除胆固醇的机制与肝细胞系和小鼠肝细胞中一样有效。第二个是确定每个相关肝受体对去除胆固醇的贡献。此信息对于选择最合适的CO疗法，例如他汀类药物将很有用。第三，我们将表明，SOF将胆固醇从巨噬细胞（在动脉粥样硬化的各个阶段）中的巨噬细胞转移到肝脏以处置。最后，我们将表明SOF逆转小鼠的动脉粥样硬化。这些目标的完成将为未来的非人类灵长类动物的研究铺平道路，并最终在高风险患者患有动脉粥样硬化的患者中铺平道路。方法：响应SOF的无线电痕量胆固醇吸收和肝细胞去除；使用色谱方法在细胞和小鼠中显示SOF促进巨噬细胞 - 胆固醇向水溶性胆汁盐的转化，这些胆汁盐进入肠道以处置；在小鼠中表征了通过化学分析和形态计量学对SOF的响应变化。

项目成果

Enhancing reverse cholesterol transport: the case for phosphatidylcholine therapy.

增强反向胆固醇转运：磷脂酰胆碱治疗的案例。

• DOI: 10.1097/01.mol.0000169345.15450.4b
• 发表时间: 2005
• 期刊: Current opinion in lipidology
• 影响因子: 4.4
• 作者: Pownall,HenryJ;Ehnholm,Christian
• 通讯作者: Ehnholm,Christian

Role of cysteine residues in human plasma phospholipid transfer protein.

半胱氨酸残基在人血浆磷脂转移蛋白中的作用。

• DOI: 10.1023/a:1020628006453
• 发表时间: 1999
• 期刊: Journal of protein chemistry
• 作者: Qu,SJ;Fan,HZ;Kilinc,C;Pownall,HJ
• 通讯作者: Pownall,HJ

Modest diet-induced weight loss reduces macrophage cholesterol efflux to plasma of patients with metabolic syndrome.

• DOI: 10.1016/j.jacl.2013.05.004
• 发表时间: 2013-11
• 期刊: Journal of clinical lipidology
• 影响因子: 4.4
• 作者: Vasudevan M;Tchoua U;Gillard BK;Jones PH;Ballantyne CM;Pownall HJ
• 通讯作者: Pownall HJ

Regulation of acyl-coenzyme A:cholesterol acyltransferase (ACAT) synthesis, degradation, and translocation by high-density lipoprotein(2) at a low concentration.

低浓度高密度脂蛋白 (2) 对酰基辅酶 A：胆固醇酰基转移酶 (ACAT) 合成、降解和易位的调节。

• DOI: 10.1161/01.atv.20.12.2636
• 发表时间: 2000
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Li,L;Pownall,HJ
• 通讯作者: Pownall,HJ

Pro-apoptotic low-density lipoprotein subfractions in type II diabetes.

II 型糖尿病中促凋亡的低密度脂蛋白亚组分。

• DOI: 10.1016/j.atherosclerosis.2006.08.059
• 发表时间: 2007
• 期刊: Atherosclerosis
• 影响因子: 5.3
• 作者: Yang,Chao-yuh;Chen,Hsin-Hung;Huang,MaxT;Raya,JoeL;Yang,Jun-Hai;Chen,Chu-Huang;Gaubatz,JohnW;Pownall,HenryJ;Taylor,AddisonA;Ballantyne,ChristieM;Jenniskens,FloorA;Smith,CharlesV
• 通讯作者: Smith,CharlesV