Human Atherogenesis with Underlying Dysfunctional HDL-Free Cholesterol

人类动脉粥样硬化与潜在的高密度脂蛋白胆固醇功能失调

• 批准号: 10653634
• 负责人: Khurram Nasir
• 金额: $ 76.55万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-04 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653634
• 关键词: Affect; Animal Model; Animals; Arterial Fatty Streak; Atherosclerosis; Biological Availability; Biological Markers; Calcium; Cardiovascular Diseases; Cholesterol; Cholesterol Esters; Code; Coronary; Data; Development; Diagnosis; Diagnostic; Disease model; Dose; Esterification; Etiology; Foam Cells; Formulation; Goals; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Intervention; Link; Lipids; Lipoproteins; Low-Density Lipoproteins; Macrophage; Measures; Metabolic; Metabolic Diseases; Metabolism; Methods; Modeling; Molecular; Mus; Mutation; Nuclear Magnetic Resonance; Patient Transfer; Patients; Persons; Phenotype; Phosphatidylcholine-Sterol O-Acyltransferase; Physicians; Physiological; Plasma; Predictive Value; Probucol; Process; Proteins; Reporting; Residual state; Risk; Risk Factors; Role; Severities; Source; Subgroup; Sum; Testing; Validation; Wild Type Mouse; athero susceptible; atherogenesis; atheroprotective; cardiovascular disorder risk; cell type; coronary calcium scoring; disease diagnostic; effective therapy; genetic variant; high density lipoprotein receptor; indexing; inhibitor therapy; mortality; overexpression; particle; response; reverse cholesterol transport; therapeutic development; trend; validation studies; Affect; Animal Model; Animals; Arterial Fatty Streak; Atherosclerosis; Biological Availability; Biological Markers; Calcium; Cardiovascular Diseases; Cholesterol; Cholesterol Esters; Code; Coronary; Data; Development; Diagnosis; Diagnostic; Disease model; Dose; Esterification; Etiology; Foam Cells; Formulation; Goals; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Intervention; Link; Lipids; Lipoproteins; Low-Density Lipoproteins; Macrophage; Measures; Metabolic; Metabolic Diseases; Metabolism; Methods; Modeling; Molecular; Mus; Mutation; Nuclear Magnetic Resonance; Patient Transfer; Patients; Persons; Phenotype; Phosphatidylcholine-Sterol O-Acyltransferase; Physicians; Physiological; Plasma; Predictive Value; Probucol; Process; Proteins; Reporting; Residual state; Risk; Risk Factors; Role; Severities; Source; Subgroup; Sum; Testing; Validation; Wild Type Mouse; athero susceptible; atherogenesis; atheroprotective; cardiovascular disorder risk; cell type; coronary calcium scoring; disease diagnostic; effective therapy; genetic variant; high density lipoprotein receptor; indexing; inhibitor therapy; mortality; overexpression; particle; response; reverse cholesterol transport; therapeutic development; trend; validation studies

Atherosclerotic cardiovascular disease (ASCVD) and plasma high-density lipoprotein cholesterol (HDL-C) are negatively correlated. One model assigns this correlation to the role of HDL as an acceptor of free cholesterol (FC) transfer from arterial-wall macrophages (FC efflux), and in some studies, FC efflux better predicted ASCVD than HDL-C concentration. However, interventions that increase plasma HDL failed to reduce ASCVD, and, paradoxically, several studies revealed higher ASCVD mortality among patients with very high HDL. The source of this paradox is unknown, appropriate therapies have not been formulated, and in this context, the role of the reverse process, HDL-FC influx, which may be supported by excess HDL-FC, is unknown. Mice deficient in the HDL-receptor, Scarb1-/- mice, are a robust model of the human high-HDL phenotype. Compared to wild-type mice, Scarb1-/- mice are more athero-susceptible and have higher plasma levels of HDL that is more FC-rich. This produces a state of high HDL-FC bioavailability, which we express as an index: HDL- FCBI = HDL particle number (HDL-P) x mol% HDL-FC. This conceptually new metric was first reported by this study team, which reported that HDL-FCBI increases as wild-type mice < human << Scarb1-/- mice and that more FC transfers from HDL from Scarb1-/- vs. wild-type mice to macrophages. Thus, we hypothesize that similar mechanisms underlie ASCVD among humans with very high plasma HDL-C. Our goal is to compare patients with positive (CACS>0) and negative (CACS=0) coronary artery calcium scores respectively assigned as ASCVD and non-ASCVD in three subgroups—those with high (HH), intermediate (IH), or optimal (OH) plasma HDL-C concentrations—and test whether ASCVD is associated with a high HDL-FCBI. According to our hypothesis, a) HDL-FCBI will be higher among HH vs. OH patients and among ASCVD vs. non-ASCVD patients, especially those with high plasma HDL-C, and b) the magnitude of FC transfer from HDL from ASCVD patients to macrophages will be greater than that from HDL from non-ASCVD patients, again especially among ASCVD patients with high plasma HDL-C. This hypothesis is supported by studies of Scarb1-/- mice in which a component of HDL-FCBI is reduced and with it, ASCVD—reducing HDL-P with probucol or mol% HDL-FC by increased FC esterification suppressed ASCVD. Comparison of CACS vs. HDL- FCBI of all three groups will reveal a non-linear functional relationship. Traditionally, physicians have measured HDL and LDL in terms of their total cholesterol content. These measures have had good but imperfect predictive value, mainly because the two components of TC, FC and cholesteryl esters, have distinct metabolic itineraries that may differentially contribute to ASCVD. Validation of the study-hypotheses in humans would provide a compelling rationale for measuring plasma lipoprotein FC as an ASCVD diagnostic and for the formulation of therapies that reduce plasma- and especially HDL-FC.

动脉粥样硬化心血管疾病（ASCVD）和血浆高密度脂蛋白胆固醇（HDL-C）为 负相关。一种模型将这种相关性分配给HDL作为自由胆固醇的受体的作用 （FC）从人工制品（FC外排）转移，在某些研究中，FC外排更好地预测 ASCVD大于HDL-C浓度。但是，增加血浆HDL的干预措施未能减少ASCVD， 而且，矛盾的是，几项研究表明，HDL非常高的患者的ASCVD死亡率较高。 该悖论的来源未知，尚未制定适当的疗法，在这种情况下， 反向过程的作用，HDL-FC的影响可能由过量的HDL-FC支持。老鼠 缺乏HDL受体Scarb1 - / - 小鼠是人类高HDL表型的强大模型。 与野生型小鼠相比，Scarb1 - / - 小鼠更容易触及，血浆水平较高 那是更丰富的FC。这会产生高HDL-FC生物利用度的状态，我们表示为索引：HDL- FCBI = HDL粒子数（HDL-P）x mol％HDL-FC。从概念上讲，这个新的指标首先报道了 研究团队报告说，HDL-FCBI随着野生型小鼠的增加而增加，<< scarb1 - / - 小鼠， 从SCRB1 - / - 与野生型小鼠到巨噬细胞的HDL更多的FC转移。那我们假设 血浆HDL-C非常高的人类ASCVD的类似机制。我们的目标是比较 分别分配了阳性（CAC> 0）和阴性（CACS = 0）冠状动脉钙评分的患者 作为三个亚组中的ASCVD和非ASCVD，即高（HH），中级（IH）或最佳（OH）的ASCVD和非ASCVD 血浆HDL-C浓度 - 测试ASCVD是否与高HDL-FCBI相关。根据 我们的假设，HH与OH患者以及ASCVD与非ASCVD中的HHDL-FCBI将更高 患者，尤其是血浆HDL-C高的患者，b）从HDL转移的大小 ASCVD患者到巨噬细胞的患者将大于非ASCVD患者的HDL，再次 特别是在具有高血浆HDL-C的ASCVD患者中。该假设得到了对 SCARB1 - / - 小鼠，其中HDL-FCBI的成分减少了，随之而来的是ASCVD，将HDL-P降低了 通过增加FC酯化抑制ASCVD，procucol或Mol％HDL-FC。 CACS与HDL-的比较 这三个组的FCBI将揭示非线性功能关系。 传统上，医生根据其总胆固醇含量测量了HDL和LDL。这些 措施具有良好但不完美的预测价值，主要是因为TC，FC和 胆固醇酯具有明显的代谢行线，可能对ASCVD有所不同。验证 人类的研究 - 假设将为测量血浆脂蛋白FC作为AS的引人注目的理由 ASCVD诊断和用于减少血浆，尤其是HDL-FC的疗法的制定。