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)是 负相关。一种模型将这种相关性归因于高密度脂蛋白作为游离胆固醇受体的作用 (FC)从动脉壁巨噬细胞转移(FC外流)，在一些研究中，FC外流可以更好地预测 ASCVD高于高密度脂蛋白胆固醇浓度。然而，增加血浆高密度脂蛋白的干预未能减少ASCVD， 而且，矛盾的是，几项研究显示，在高密度脂蛋白水平非常高的患者中，ASCVD的死亡率更高。这个 这一悖论的根源不明，还没有制定适当的治疗方法，在这方面， 反之，可能由过量的高密度脂蛋白胆固醇支持的高密度脂蛋白胆固醇流入，其作用尚不清楚。老鼠 缺乏高密度脂蛋白受体的Scar1-/-小鼠是人类高高密度脂蛋白表型的健壮模型。 与野生型小鼠相比，Scar1-/-小鼠更容易患动脉粥样硬化，并且血浆高密度脂蛋白水平更高 这是更丰富的FC。这产生了高密度脂蛋白-FC生物利用度的状态，我们将其表示为一个指数：高密度脂蛋白-- FCBI=高密度脂蛋白颗粒数(高密度脂蛋白-P)x摩尔百分比高密度脂蛋白-Fc。这一概念上的新指标首先由以下人员报道 研究小组报告说，高密度脂蛋白-FCBI作为野生型小鼠和人；斯卡伯1-/-鼠增加 与野生型小鼠相比，更多的Fc从Scar1-/-小鼠的高密度脂蛋白转移到巨噬细胞。因此，我们假设 在血浆高密度脂蛋白胆固醇水平非常高的人群中，ASCVD的发生机制与此类似。我们的目标是比较 冠状动脉钙化积分阳性(CACS&GT；0)和阴性(CACS=0)的患者分别被分配 作为ASCVD和非ASCVD的三个亚组-高(HH)、中(IH)或最佳(OH) 血浆高密度脂蛋白-C浓度-并测试ASCVD是否与高密度脂蛋白-FCBI相关。根据 我们的假设是，a)高密度脂蛋白-FCBI在HH与OH患者之间以及ASCVD与非ASCVD患者之间将更高 患者，特别是那些血浆高密度脂蛋白-C的患者，以及b)从高密度脂蛋白转移到 ASCVD患者对巨噬细胞的作用将再次大于非ASCVD患者的高密度脂蛋白 尤其是血浆高密度脂蛋白胆固醇升高的ASCVD患者。这一假设得到了以下研究的支持 Scar1-/-小鼠体内高密度脂蛋白-FCBI的一种成分减少，随之而来的是ASCVD-通过 普罗布考或增加FC酯化程度的摩尔%高密度脂蛋白胆固醇可抑制ASCVD。CACS与高密度脂蛋白的比较 三组的FCBI均呈非线性函数关系。 传统上，医生用总胆固醇含量来测量高密度脂蛋白和低密度脂蛋白。这些 指标具有良好但不完美的预测价值，主要是因为TC、FC和FC的两个组成部分 胆固醇酯有不同的代谢路线，可能对ASCVD有不同的贡献。验证 这项在人类中的研究假设将为测量血浆脂蛋白Fc作为 ASCVD的诊断和降低血浆，特别是高密度脂蛋白-FC的治疗方法的配方。