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

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.

动脉粥样硬化性心血管疾病 (ASCVD) 和血浆高密度脂蛋白胆固醇 (HDL-C) 一种模型将这种相关性归因于 HDL 作为游离胆固醇受体的作用。 (FC) 从动脉壁巨噬细胞转移（FC 流出），在一些研究中，FC 流出更好地预测 ASCVD 高于 HDL-C 浓度 然而，增加血浆 HDL 的干预措施未能降低 ASCVD、 矛盾的是，一些研究显示高密度脂蛋白水平极高的患者 ASCVD 死亡率更高。 这种悖论的根源尚不清楚，尚未制定适当的治疗方法，在这种情况下， HDL-FC 流入的相反过程的作用（可能由过量的 HDL-FC 支持）尚不清楚。 缺乏 HDL 受体的 Scarb1-/- 小鼠是人类高 HDL 表型的稳健模型。 与野生型小鼠相比，Scarb1-/- 小鼠更容易发生动脉粥样硬化，且血浆 HDL 水平更高 这会产生高 HDL-FC 生物利用度的状态，我们将其表示为指数：HDL-。 FCBI = HDL 颗粒数 (HDL-P) x mol% HDL-FC 这一概念性新指标首次由本报告报道。 研究小组报告称，HDL-FCBI 随着野生型小鼠 < 人类 << Scarb1-/- 小鼠的增加而增加，并且 与野生型小鼠相比，Scarb1-/- 的 HDL 向巨噬细胞的 FC 转移更多。 血浆 HDL-C 非常高的人类 ASCVD 具有相似的机制，我们的目标是进行比较。 冠状动脉钙化评分阳性（CACS>0）和阴性（CACS=0）的患者分别分配 ASCVD 和非 ASCVD 分为三个亚组——高 (HH)、中 (IH) 或最佳 (OH) 血浆 HDL-C 浓度——并测试 ASCVD 是否与高 HDL-FCBI 相关。 我们的假设，a) HH 患者与 OH 患者以及 ASCVD 与非 ASCVD 患者中 HDL-FCBI 会更高 患者，尤其是那些血浆 HDL-C 较高的患者，以及 b) 从 HDL 转移至 FC 的程度 ASCVD 患者的巨噬细胞摄入量将再次大于非 ASCVD 患者的 HDL 摄入量 特别是在血浆 HDL-C 较高的 ASCVD 患者中，这一假设得到了以下研究的支持。 Scarb1-/- 小鼠的 HDL-FCBI 成分减少，ASCVD 减少 HDL-P 普罗布考或 mol% HDL-FC 通过增加 FC 酯化抑制了 CACS 与 HDL- 的比较。 所有三组的 FCBI 将揭示非线性函数关系。 传统上，医生根据总胆固醇含量来测量高密度脂蛋白和低密度脂蛋白。 措施具有良好但不完善的预测价值，主要是因为 TC、FC 和 胆固醇酯具有不同的代谢行程，可能对 ASCVD 产生不同的影响。 人类研究假设将为测量血浆脂蛋白 FC 提供令人信服的理由： ASCVD 诊断以及制定降低血浆尤其是 HDL-FC 的疗法。