High-Density Lipoprotein and Atherosclerosis: The Role of Antioxidant Activity

Levels of high-density lipoprotein (HDL) cholesterol are generally inversely associated with the risk for the development of atherosclerosis. The mechanism by which HDL imparts protection from the initiation and progression of occlusive vascular disease is complex and multifactorial. The major anti-atherosclerotic effect of HDL is felt to be reverse cholesterol transport. HDL has been demonstrated to scavenge cholesterol from the peripheral vasculature with transport to the liver, where is it excreted in the biliary system. However, HDL exhibits multiple other physiologic effects that may play a role in the reduced risk for atherosclerosis. HDL has been demonstrated to exhibit beneficial effects on platelet function, endothelial function, coagulation parameters, inflammation, and interactions with triglyceride-rich lipoproteins. Increasing amounts of clinical and experimental data have shown that HDL cholesterol has significant antioxidant effect that may significantly contribute to protection from atherosclerosis.     

载脂蛋白M与高密度脂蛋白代谢及动脉粥样硬化

栽脂蛋白(apo)M是一种新近发现的载脂蛋白,蛋白结构属于Lipocalin超家族成员,它含有一个特征性的疏水结合盒,成熟的apoM保留了具有"疏水锚"作用的信号肽,apoM很可能通过此信号肽锚着在高密度脂蛋白(HDL)磷脂单层.动物实验发现apoM的缺失会导致血浆前β-高密度脂蛋白的消失和异常犬的HDL颗粒的出现.在低密度脂蛋白受体缺陷小鼠,腺病毒致肝脏apoM的过度表达可使动脉粥样硬化病变明显减少.现有研究表明apoM可调节HDL代谢,并具有抗动脉粥样硬化的作用.     

Evolving Concepts of the Role of High-Density Lipoprotein in Protection from Atherosclerosis

High-density lipoprotein (HDL) is classified as a negative risk factor due to the inverse relationship between elevated levels of HDL cholesterol and atherosclerosis. The mechanism by which HDL can mediate protection from atherosclerosis is complex and multifactorial. The primary role of reverse cholesterol transport in the reduction of risk for coronary artery disease is supported by a considerable amount of experimental data. HDL is able to interact with and remove cholesterol from the lipid-laden foam cells in the peripheral vasculature with subsequent transportation to the liver for excretion. However, HDL has multiple other physiologic effects that may play a significant role in protection from atherosclerosis. HDL has been demonstrated to exhibit multiple beneficial effects on the coagulation system. Platelet function is improved by both direct and indirect mechanisms. HDL has a complex interaction with the protein C and protein S system. Thrombolytic balance is also improved by HDL. HDL has been demonstrated to have a significant natural antioxidant effect that inhibits the oxidative step required for low-density lipoprotein uptake by the macrophage. Additionally, HDL has also been demonstrated to exert multiple beneficial effects on endothelial function, including decreased apoptosis and endothelial repair.     

Recombinant High-Density Lipoprotein Formulations

High-density lipoprotein cholesterol (HDL-C) has emerged as a biomarker of residual cardiovascular disease (CVD) risk in high-risk patients treated with low-density lipoprotein cholesterol (LDL-C)-lowering therapies inclusive of inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase. The evidence for increasing low levels of HDL-C is sparse, and the available data are confounded by metabolic interactions between elevated very low-density lipoprotein (VLDL) and LDL particle concentrations. Despite these limitations, there has been widespread interest in novel strategies that target HDL. One such path has been the development of recombinant HDL formulations that mimic the pre-beta fraction of native HDL, which is the main HDL subclass that mediates cholesterol efflux from lipid-laden macrophages. Various recombinant HDL formulations (apolipoprotein A-1 [apoA-1]-bound phospholipid disks or delipidated HDL particles, mutant apoA-1 proteins, and apoA-1 mimetic peptides) have been investigated in animal studies and some human trials. However, these HDL-modifying therapies require evaluation in clinical trials of atherosclerosis and CVD events. This review presents our current knowledge on novel recombinant therapies, and their future prospects to mitigate atherosclerotic CVD events.     

Speciated High-Density Lipoprotein Biogenesis and Functionality

Plasma high-density lipoprotein cholesterol (HDL-C) concentration is a negative risk factor for atherosclerotic cardiovascular disease (CVD). Despite this, most attempts to raise plasma HDL-C concentrations in a cardioprotective way have failed. Recently, hypotheses about the atheroprotective effects of HDL have shifted away from quantity to quality, mostly HDL function in reverse cholesterol transport. Plasma HDL from CVD patients is a poorer acceptor of cellular cholesterol than plasma from healthy controls, independent of plasma HDL-C concentrations. The function of HDL is likely determined by two other factors, stability and composition. The kinetic instability of HDL, which varies according to subclass, is a likely determinant of its reactivity in response to many HDL-modifying activities. HDL composition is also heterogeneous and variable; all HDL particles contain apo AI but only about two-thirds contain apo AII. This occurs despite the fact that apo AI and apo AII are hepatically secreted on separate HDL that later fuse in plasma. HDL also contains traces of other proteins, some of which have not yet been associated with HDL function. One minor HDL species are those that are secreted with intact signal peptides, which enhances their binding to HDL; these HDL have special properties that are independent of cholesterol transport. Here, we review and provide a perspective about what is currently known about speciated HDL biogenesis in the context of health and disease.     

血浆高密度脂蛋白水平低下的治疗方法研究进展

血浆中高密度脂蛋白水平与动脉粥样硬化的发病呈负相关,低高密度脂蛋白水平是冠心病的独立危险因素,要进一步降低心脑血管疾病发生率,在降低低密度脂蛋白的同时,还必须加强对高密度脂蛋白的干预。现主要论述升高高密度脂蛋白水平,提高高密度脂蛋白功能的治疗方法研究进展。     

高密度脂蛋白胆固醇与心血管剩余风险

血脂异常是动脉粥样硬化的最主要危险因素之一.从20世纪60年代开始,大量的降低胆固醇临床试验均为“越低越好”的降脂理念奠定了坚固的循证医学基石.他汀类药物可通过降低低密度脂蛋白胆固醇而显著减低心血管事件发生.然而在一些低密度脂蛋白胆固醇已经达标,甚至已降至70 mg/dL以下的患者中,仍然存在着较高的心血管剩余风险.低水平的高密度脂蛋白胆固醇是其最主要的原因之一.因此目前,即使大剂量的强化他汀治疗仍不能完全解决剩余风险的存在.而解决剩余风险的存在对进一步降低心血管病患者的风险又尤为重要.文章主要就高密度脂蛋白胆固醇与心血管剩余风险之间的关系及最新研究进展作进一步归纳和阐述.     

High-Density Lipoprotein Processing and Premature Cardiovascular Disease

High plasma concentrations of low-density lipoprotein-cholesterol (LDL-C) are a well-accepted risk factor for cardiovascular disease (CVD), and the statin class of hypolipidemic drugs has emerged as an effective means of lowering LDL-C and reducing CVD risk. In contrast, the role of plasma high-density lipoproteins (HDL) in protection against atherosclerotic vascular disease is the subject of considerable controversy. Although the inverse correlation between plasma HDL-C and CVD is widely acknowledged, reduction of CVD risk by interventions that increase HDL-C have not been uniformly successful. Several studies of large populations have shown that the first step in reverse cholesterol transport (RCT), the transfer of cholesterol from the subendothelial space of the arterial wall via the plasma compartment to the liver for disposal, is impaired in patients with CVD. Here we review HDL function, the mechanisms by which HDL supports RCT, and the role of RCT in preventing CVD.     

氧化低密度脂蛋白与动脉粥样硬化

氧化低密度脂蛋白是动脉粥样硬化的关键因子,其在动脉粥样硬化病变发生的中心地位已经确立.临床上已经开始关注其对冠心病患者的检出率和预后评估.     

High-Density Lipoprotein Functionality in Coronary Artery Disease

The role of high-density lipoprotein (HDL) in cardiovascular atheroprotection is well established. Epidemiological data have clearly demonstrated an inverse relationship between HDL levels and the risk for coronary artery disease, which is independent of the low-density lipoprotein levels. However, more recent data provide evidence that high HDL levels are not always protective and that under certain conditions may even confer an increased risk. Thus, a new concept has arisen, which stresses the importance of HDL functionality, rather than HDL concentration per se, in the assessment of cardiovascular risk. HDL functionality is genetically defined but can also be modified by several environmental and lifestyle factors, such as diet, smoking or certain pharmacologic interventions. Furthermore, HDL is consisted of a heterogeneous group of particles with major differences in their structural, biological and functional properties. Recently, the cholesterol efflux capacity from macrophages was proven to be an excellent metric of HDL functionality, because it was shown to have a strong inverse relationship with the risk of angiographically documented coronary artery disease, independent of the HDL and apolipoprotein A-1 levels, although it may not actually predict the prospective risk for cardiovascular events. Thus, improving the quality of HDL may represent a better therapeutic target than simply raising the HDL level, and assessment of HDL function may prove informative in refining our understanding of HDL-mediated atheroprotection.     

Effects of Diet on High-Density Lipoprotein Cholesterol

Multiple dietary factors have been shown to increase high-density lipoprotein cholesterol (HDL-C) concentrations, and HDL-C has been inversely associated with coronary heart disease (CHD) risk. Replacement of dietary carbohydrate with polyunsaturated, monounsaturated and saturated fat has been associated with progressively greater increases in HDL-C (7–12%) in addition to other lipid changes. Added sugars, but not high glycemic carbohydrates, have been associated with decreased HDL-C. Alcohol consumption has been associated with increased HDL-C (9.2%) independent of changes in other measured lipids. Modest effects on HDL-C (~4–5%) among other lipid and non-lipid CHD risk factors have also been observed with weight loss by dieting, omega-3 fatty acids, and a Mediterranean diet pattern. The CHD benefit of increasing HDL-C is unclear given the inconsistent evidence from HDL-raising pharmacologic trials. Furthermore, pleiotropic effects of diet preclude attribution of CHD benefit specifically to HDL-C. Investigation into functional or other properties of HDL may lend further insight.     

Association of Total Cholesterol/High-Density Lipoprotein Cholesterol Ratio With Proximal Coronary Atherosclerosis Detected by Multislice Computed Tomography

The authors assessed the association between an elevated total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio (≥4) and proximal coronary artery disease (CAD), as observed on multislice computed tomography. Coronary multislice computed tomographic angiography (96% on 40- or 64-slice) was performed in 295 individuals (39% women; mean age, 54±13 years) without documented CAD who were referred for coronary evaluation. Significant CAD was defined as ≥50% stenosis in the left main, proximal left anterior descending, or ≥2 epicardial vessels. Proximal plaque was defined as presence of any plaque in left main or proximal left anterior descending vessels. Individuals with an elevated TC/HDL-C ratio vs those without had a higher prevalence of proximal plaque (62% vs 48%, P =.04) and significant CAD (19% vs 9%, P =.009). On multivariate logistic regression analysis, only age, sex, and TC/HDL-C ratio ≥4 were associated with significant CAD and proximal plaque.     

升高高密度脂蛋白胆固醇药物的相关研究进展

目前已有流行病学资料明确提示,高密度脂蛋白胆固醇(HDL-C)水平与冠心病危险性呈负相关,低水平的HDL-C已被公认为动脉粥样硬化性疾病的独立危险因素之一。通过药物使HDL-C升高能否进一步降低心血管疾病的发病风险已成为近些年来临床试验关注的焦点。本文对目前已应用于临床或正在研究的具有升高HDL-C作用的四类药物,即他汀类、贝特类、烟酸及胆固醇酯转运蛋白(CETP)抑制剂的主要作用机制、临床研究进展等进行归纳和总结。其中,烟酸及CETP抑制剂升高HDL-C作用显著,尽管目前针对这两类药物的临床证据仍然较为匮乏,但有理由相信正在进行的几项国际大规模临床试验将为此提供重要的询证医学证据,其结果值得期待。     

血凝素样氧化低密度脂蛋白受体-1与动脉粥样硬化

血凝素样氧化低密度脂蛋白受体-1(LOX-1)是氧化低密度脂蛋白(ox-LDL)的特异性受体,结构上属C型血凝素家族,通过介导ox-LDL对血管内皮细胞的损伤参与动脉粥样硬化的形成和发展过程.本文就LOX-1的生物学特性、表达和调节因素及其与动脉粥样硬化的关系进行综述.