Molecular Mechanisms for Dysfunctional High Density Lipoprotein (HDL)

高密度脂蛋白 (HDL) 功能失调的分子机制

• 批准号: 7457754
• 负责人: JAY W HEINECKE
• 金额: $ 38.01万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7457754
• 关键词: 3-chlorotyrosine; ATP-Binding Cassette Transporters; Address; Affect; Age; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Antioxidants; Apolipoprotein A-I; Apolipoproteins; Apolipoproteins A; Arteries; Atherosclerosis; Biology; Blood specimen; Cardiovascular Diseases; Carotid Artery Diseases; Case-Control Studies; Cause of Death; Cell membrane; Cells; Cholesterol; Complement; Condition; Goals; High Density Lipoproteins; Human; Hypochlorous Acid; Hypochlorous Acids; In Vitro; Inflammation; Inflammatory; Isotopes; Lead; Least-Squares Analysis; Lipids; Mass Spectrum Analysis; Mediating; Membrane Transport Proteins; Methods; Modification; Molecular; Monitor; Mus; Natural regeneration; Oxidants; Pathway interactions; Patients; Pattern Recognition; Peptides; Peroxidase; Phagocytes; Phospholipids; Physiological; Plasma; Population; Principal Component Analysis; Process; Property; Prospective Studies; Protease Inhibitor; Proteins; Proteomics; Reaction; Research Personnel; Resources; Risk; Role; Serine; Serpins; Shotguns; Site; Societies; Study Subject; System; Testing; Therapeutic; Tyrosine; Vitronectin; aryldialkylphosphatase; atherogenesis; atheroprotective; cardiovascular disorder risk; chlorination; complement C3 precursor; genetic regulatory protein; human disease; in vivo; lipid metabolism; macrophage; men; novel diagnostics; oxidation; particle; prevent; programs; prospective; reverse cholesterol transport; sex; sulfated glycoprotein 2

DESCRIPTION (provided by applicant): It is widely believed that high density lipoprotein (HDL) protects against atherosclerosis by removing excess cholesterol from arterial cells. Recent studies indicate that HDL is also anti-inflammatory and inhibits lipid oxidation in vivo. These properties may contribute significantly to HDL's ability to inhibit atherosclerosis. Inflammation has been proposed to convert HDL to a dysfunctional form that loses these antiatherogenic effects. Understanding the role of dysfunctional HDL may lead to new diagnostic and therapeutic approaches to atherosclerosis and other inflammatory conditions. However, the underlying factors that render HDL dysfunctional remain poorly understood. One important pathway may involve oxidative damage to HDL by myeloperoxidase (MPO). We have shown that oxidation of apoA-l by MPO impairs the apolipoprotein's ability to remove cellular cholesterol by the ABCA1 pathway, and that HDL is targeted for damage by MPO in vivo. Furthermore, remarkably little is known regarding the identity of proteins that are carried in normal and dysfunctional HDL. We have used shotgun proteomics to test the hypothesis that HDL might carry proteins that make a previously unsuspected contribution to its cardioprotective activity. Our observations suggest that HDL carries a unique cargo of proteins in CVD subjects and that these proteins might make previously unsuspected contributions to the pro- and anti-inflammatory properties of HDL. We therefore propose to test the hypothesis that site-specific oxidation of apoA-l by MPO and deleterious alterations in the protein composition of HDL are molecular mechanisms for generating dysfunctional HDL in humans. Our specific aims are: i) Establish whether apolipoprotein A-l of HDL is targeted for oxidation in humans at risk for cardiovascular disease, ii) Determine whether site-specific oxidation of apoA-l in humans associates with loss of the apolipoprotein's ability to remove cellular cholesterol by the ABCA1 and ABCG1 pathways, iii) Determine whether pro- and anti-inflammatory proteins help generate dysfunctional HDL in humans.

描述（由申请人提供）：人们普遍认为高密度脂蛋白（HDL）通过清除动脉细胞中多余的胆固醇来预防动脉粥样硬化。最近的研究表明，HDL在体内也具有抗炎和抑制脂质氧化的作用。这些特性可能有助于HDL抑制动脉粥样硬化的能力。炎症已被提出将HDL转化为功能失调的形式，失去这些抗动脉粥样硬化作用。