Atheroprotective effects of HDL: beyond reverse cholesterol transport

The risk of atherosclerosis is inversely related to circulating levels of high density lipoprotein (HDL) cholesterol. Notably, in large-scale epidemiologic studies, this association is independent of plasma levels of low density lipoprotein cholesterol levels. Pharmacologic agents, such as fibrates and niacin that increase HDL cholesterol levels have been associated with decreased cardiovascular events and beneficial effects on the coronary and carotid arteries. Furthermore, there is evidence that the risk of restenosis following vascular interventions is inversely related to HDL levels. This review considers the available data from mainly murine models on potential mechanisms by which HDL may exert these anti-atherogenic effects, namely through its role in reverse cholesterol transport, its effects on endothelial cells, and its anti-inflammatory/anti-oxidant activities. In addition to discussing a role for HDL in retarding atherosclerosis progression, we will also review how HDL may play a role in promoting regression of atherosclerotic lesions.     

Signal transduction pathways

The development of agents designed to interfere with the various signal transduction pathways known to be aberrant in cancers remains an interesting area of anticancer drug development. The ability to identify a large series of kinase inhibitors with differing selectivities has been one of the major recent advances in medicinal chemistry. A series of first generation inhibitors of cyclin-dependent kinases, specific tyrosine kinases, (as well as inhibitors of processing of the Ras protein, which were not covered in this session) have now reached early clinical trials. In contrast to trials with "standard" cytotoxic agents, cytostatic effects necessitating the use of chronic, ideally oral, dosing schedules is the norm for these new agents.     

Signal transduction pathways in mitogenesis

Quiescent cells arrested in the Go phase of the cell cycle can be stimulated to divide by polypeptide growth factors, pharmacological agents and neuropeptides which exhibit potent synergistic effects. Bombesin-like peptides are providing valuable model mitogens to elucidate the signalling pathways leading to mitogenesis. These peptides stimulate rapid increases in ionic fluxes, inositol polyphosphate formation, activation of protein kinases and expression of proto-oncogenes. A comparison of these early molecular events with those evoked by other growth factors indicate the existence of multiple signal-transduction pathways. We propose that stimulation of cell proliferation by single or multiple factors results from the activation of separate signal-transduction pathways that cooperate to elicit the complete set of molecular events leading to mitogenesis.     

二甲双胍介导胆固醇逆转运抑制动脉粥样硬化

目的探讨二甲双胍通过对胆固醇逆转运抑制ApoE^-/-小鼠动脉粥样硬化的分子机制。方法18只ApoE^-/-小鼠随机分为三组,对照组、模型组和二甲双胍组,每周监测体质量变化。取血检测血清血脂水平;小动物超声检测腹主动脉管壁厚度;HE和油红O染色评价肝脏脂肪病变程度;Western blot检测肝脏胆固醇逆转运相关蛋白LXRɑ、ABCA1的表达。结果与对照组比,模型组体质量、血清TC、TG、LDL升高,HDL降低(P<0.05),腹主动脉管壁增厚(P<0.05),肝脏脂肪沉积加重及LXRɑ、ABCA1的表达降低。二甲双胍组体质量、血清TC、TG、LDL降低,HDL升高(P<0.05),肝脏脂肪沉积及腹主动脉管壁厚度显著减轻(P<0.05),LXRɑ、ABCA1表达显著增高(P<0.05)。结论二甲双胍通过上调肝脏胆固醇逆向转运相关蛋白LXRɑ和ABCA1的表达,增强肝脏胆固醇逆转运能力,调节血脂代谢、减轻肝脏脂质沉积,从而延缓动脉粥样硬化的进展。     

Signal transduction pathways of taxanes-induced apoptosis

Docetaxel (Taxotere) is a member of the taxane class of anticancer agents to reach clinical use. This semisynthetic analog of paclitaxel (Taxol) is one of the newer potent anti-neoplastic agents now undergoing extensive laboratory and clinical investigations. Several studies indicate that antimicrotubule agents are potent promoters of apoptosis in cancer cells. Cytotoxic mechanisms of antimitotic taxoids are not yet fully understood, but it has been demonstrated that docetaxel increases tubulin polymerisation, promotes microtubule assembly and also inhibits tubulin depolymerisation. Disruption of microtubules results also in the induction of tumor suppressor gene p53 and inhibitor of cyclin-dependent kinases and activation/inactivation of several protein kinases. As a consequence cells are arrested in the G2-M phase of the cell cycle, after which they may either undergo cell death by apoptosis or necrosis or overcome the G2-M stop and continue in the division cycle (often toward a post-mitotic cell death) depending on the tumor cell type. Nevertheless, how docetaxel induces apoptotic cell death or caspases activation is not yet defined. One may assume that taxanes are able to induce the phosphorylation of Bcl-X(L)/Bcl-2 members and thus inactivate their anti-apoptotic capacities. The down-regulation of Bcl-2 and/or the upregulation of p53 and p21/WAF-1 are certainly one of the important modes of apoptosis induction by taxanes. The aim of this framework is to summarize the effects of microtubuline targeting agents on apoptotic signal transduction and new molecular pathways. Finally, we will also discuss the potential therapeutic interest in the association of docetaxel and ionizing radiation.     

免疫调节相关的信号转导通路研究现状

随着现代分子生物学的迅速发展及其在免疫学研究中的广泛应用,人们已发现多种信号转导通路与免疫调节相关。目前研究较多的主要有TLRs信号通路、JAK-STAT信号通路、T细胞活化通路、B细胞活化通路等。这些信号转导通路任何环节发生异常均会导致疾病发生。     

Modulation of high-density lipoprotein cholesterol metabolism and reverse cholesterol transport

Low high-density lipoprotein (HDL)-cholesterol (C) is an important risk factor for coronary heart disease. In vitro, HDL exerts several potentially anti-atherogenic effects including reverse cholesterol transport (RCT) from peripheral cells to the liver. Hence, raising HDL-C has become an interesting target for anti-atherosclerotic drug therapy. Levels of HDL-C and the composition of HDL subclasses in plasma are regulated by apolipoproteins, lipolytic enzymes, lipid transfer proteins, receptors, and cellular transporters. The interplay of these factors leads to RCT and determines the composition and thereby the anti-atherogenic properties of HDL. Recent findings suggest that the mechanism of HDL modification rather than a sole increase in HDL-C determines the efficacy of anti-atherosclerotic drug therapy. In several controlled and prospective intervention studies, patients with low HDL-C and additional risk factors benefited from treatment with fibrates or statins. However, in only some of the fibrate trials was prevention of coronary events in patients with low HDL-C and hypertriglyceridaemia related to an increase in HDL-C. This may be because currently available drugs increase HDL-C levels only moderately and because HDL levels per se do not necessarily correlate with the functionality of HDL. However, several novel targets to modify RCT have emerged from the recent understanding of HDL synthesis, maturation and catabolism. The four major targets for an anti-atherogenic strategy in HDL metabolism include stimulation of apoA-I synthesis and secretion, the stimulation of ABCA1 expression, the inhibition of cholesterol ester transfer protein, and the up-regulation of scavenger receptor BI. These and other modulations of HDL metabolism are thought to result in improved RCT making them attractive targets for the development of new regimens of anti-atherogenic drug therapy.     

胆固醇逆向转运过程中新靶点及其药物的研究进展

血浆高密度脂蛋白胆固醇(HDLC)拮抗动脉粥样硬化(AS)的最主要机制在于参与胆固醇逆向转运(RCT)过程。近年来,将RCT过程中几个重要蛋白质和酶类,包括apoAⅠ,ABCA1,CETP等作为新的用药靶点进行了药物干预的尝试,在调节血脂和预防AS等方面取得了良好的效果,开创了治疗该类疾病的新局面,对下一步的疾病治疗具有重要的指导作用。     

普罗布考促进小鼠体内胆固醇逆转运的研究

目的检测普罗布考干预后小鼠血清脂质,血清、肝脏及粪便中3H-胆固醇占经腹腔注射3H-胆固醇总量的百分比,探讨普罗布考对小鼠体内胆固醇逆转运的影响。方法32只C57BL/6小鼠随机分为4组,给予不同剂量普罗布考(0,0.1%,0.5%,1%W/W)添加饲料饲养4wk后,腹腔注射经ac-LDL及3H-胆固醇处理过的RAW264.7小鼠巨噬细胞悬液(0.5ml/鼠,细胞数达5.0×106,放射活性达6.2×106cpm),单笼喂养24h后取血,酶法测定血清脂质;收集血清、肝组织、0～24h粪便,分别用液闪计数仪测定3H-胆固醇含量(均以占注射总量百分比计);结果0.1%普罗布考干预4wk后总胆固醇(TC)较对照组降低34.3%,52.8%,(P<0.01),低密度脂蛋白胆固醇(LDL-C)及甘油三酯(TG)降低20%,22%,(P<0.05);0.5%和1%普罗布考降低TC,HDL-C47%,55%,(P<0.01);降低LDL-C和TG为32%,30%,(P<0.05)。腹腔注射巨噬细胞悬液24h后血清中3H-胆固醇含量呈剂量依赖性轻度降低,而肝脏和粪便中3H-胆固醇含量呈剂量依赖性明显升高,分别为20%～48%(P<0.05)和20%～84%(P<0.01)。结论普罗布考虽然降低HDL-C血浆水平,但是明显促进胆固醇的逆转运,加速了胆固醇经粪便的清除,利于动脉粥样硬化的防治。     

Nuclear receptors as potential targets for modulating reverse cholesterol transport

This review describes the role of nuclear receptors in the regulation of genes involved in cholesterol transport and synthetic modulators of these receptors. Increasing the efflux of cholesterol from peripheral cells, such as lipid-laden macrophages, through a process called reverse cholesterol transport (RCT) requires HDL. Increasing the circulating levels of HDL, as well as the efficiency of the RCT process, could result in a reduction in the development of coronary artery disease and atherosclerosis. Nuclear receptors of the RXR heterodimer family have recently been shown to regulate key genes involved in HDL metabolism and reverse cholesterol transport. These include the PPARs (peroxisome proliferator activated receptors), the LXR (liver X receptor) and the farnesoid X receptor (FXR). The synthesis of specific and potent ligands for these receptors has aided in ascertaining the physiological role of these receptors as lipid sensors and the potential therapeutic utility of modulators of these receptors in dyslipidemias and cardiovascular disease.     

Signal transduction pathways triggered by selective formylpeptide analogues in human neutrophils

Human neutrophils are highly specialised for their primary function, i.e. phagocytosis and destruction of microorganisms. Leukocyte recruitment to sites of inflammation and infection is dependent upon the presence of a gradient of locally produced chemotactic factors. The bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) was one of the first of these to be identified and is a highly potent leukocyte chemoattractant. It interacts with its receptor on the neutrophil membrane, activating these cells through a G-protein-coupled pathway. Two functional fMLP receptors have thus far been cloned and characterized, namely FPR (formyl peptide receptor) and FPRL1 (FPR like-1), with high and low affinities for fMLP, respectively. FMLP is known to activate phospholipase C (PLC), PLD, PLA2 and phosphatidylinositol-3-kinase (PI3K), and it also activates tyrosine phosphorylation. The second messengers resulting from the fMLP receptor interaction act on various intracellular kinases, including protein kinase C (PKC) and mitogen-activated protein kinases (MAPKs). The activation of these signal transduction pathways is known to be responsible for various biochemical responses which contribute to physiological defence against bacterial infection and cell disruption. This review will consider the ability of selective analogues (ligands able to discriminate between different biological responses) to activate a single spectrum of signal transduction pathways capable of producing a unique set of cellular responses, hypothesising that a distinctive imprint of signal protein activation may exist. Through more complete understanding of intracellular signaling, new drugs could be developed for the selective inflammatory blockade.     

New approaches to raising the HDL cholesterol level

Not only a high level of low-density lipoprotein (LDL) cholesterol, but also a low level of high-density lipoprotein (HDL) cholesterol, is a critical risk factor for atherosclerosis and coronary heart disease. Although fibrates and niacin can be used to improve low HDL cholesterol levels, their effect is not wholly satisfactory, so better drugs for the elevation of HDL cholesterol are desired. Among the many methods that may be used to raise HDL cholesterol levels, this review focuses on inhibitors of cholesteryl ester transfer protein (CETP) and on nuclear orphan receptor agonists that mediate the expression of ATP-binding cassette transporter 1 (ABC1).     

Blood cholesterol and HDL cholesterol in cigarette smokers.

24 cigarette smokers were investigated for their blood cholesterol and HDL cholesterol. They had elevated total cholesterol compared to age and sex matched controls. 21 smokers out of 24 had significant decrease of HDL cholesterol. It is suggested that smoking, which is a major risk factor for coronary heart disease, might act through its effect on total cholesterol and HDL cholesterol.     

Rate‐limiting factors of cholesterol efflux in reverse cholesterol transport: Acceptors and donors

1. Plasma levels of high‐density lipoprotein (HDL) are believed to be inversely related to coronary artery disease. High‐density lipoprotein plays a key role in the process of reverse cholesterol transport, by which HDL is able to extract excess cholesterol from peripheral tissues and transfer it to the liver for biliary excretion. 2. Efflux of lipids (cholesterol and phospholipids) is the first step in reverse cholesterol transport. Several cellular membrane transporters, including ABCA1 and ABCG1, as well as scavenger receptor (SR)‐BI receptor, are believed to facilitate the active efflux of cholesterol to lipid‐poor apolipoprotein A‐I and mature HDL, respectively. Furthermore, overexpression or deletion of one or more specific genes supports the view that HDL is involved in cholesterol efflux. 3. In conclusion, current evidence supports a critical role for HDL in atheroprotection via an active efflux pathway through reverse cholesterol transport, with the substantial support of appropriate functions of cell donors.