Current Pharmaceutical Design - Volume 16, Issue 13, 2010

Epidemiological studies have demonstrated for nearly 50 years that high-density lipoprotein (HDL) cholesterol levels are inversely correlated with the incidence of ischemic cardiovascular diseases. This inverse relationship is attributed to the role of HDL in reverse cholesterol transport, but may also be related to its anti-oxidative, anti-inflammatory, anti-apoptotic, or endothelial protective properties, so called pleiotropic effects. More recently, it has been demonstrated that HDL also increases endothelial progenitor cell number and function and this may contribute significantly to its atheroprotective properties, further emphasizing the pleiotropic effects of HDL. The review articles included in this issue of Current Pharmaceutical Design provide an overview on the novel insights regarding the role of HDL in reverse cholesterol transport and regarding its pleiotropic effects. Furthermore, they address how HDL, under pathological conditions such as diabetes mellitus, can change from an anti-inflammatory to a pro-inflammatory particle and lose its protective properties, and discuss the implications of this finding for HDL-directed therapies. The first review by Meurs et al. [1] gives an overview of the current knowledge on the biological activities of the major apolipoproteins, enzymes, lipid transfer proteins, receptors, and lipid transporters associated with HDL function and levels, and their influence on reverse cholesterol transport. In addition, actual views on the molecular mechanisms underlying the atheroprotective functions of HDL beyond promotion of reverse cholesterol transport, including the anti-oxidant, anti-thrombotic, anti-inflammatory and anti-apoptotic properties of HDL are summarized. With respect to the pleiotropic effects of HDL, the review of Tolle et al. [2] addresses the role of HDL-associated sphingosine-1- phosphate as mediators of known protective pleiotropic features of HDL and their possible therapeutic relevance. Endothelial dysfunction is thought to play a critical role in the development and progression of atherosclerosis. Besler et al. [3] summarize the HDL-mediated direct endothelial-protective effects, including the novel observations that HDL may stimulate endothelial repair processes, involving mobilisation and promotion of endothelial repair capacity of endothelial progenitor cells. Importantly, the authors also address the recent finding that the vascular-protective effects of HDL may be variable, i.e. the capacity of HDL to stimulate macrophage cholesterol efflux and endothelial-protective effects may be altered in patients with inflammatory or cardiovascular disease. The further characterisation of the underlying mechanisms and the identification of the clinical relevance of this “HDL dysfunction” are currently an active field of research. Calabresi et al. [4] give attention to the current knowledge on the structural and functional heterogeneity of HDL particles, and their relationship to cardiovascular disease, in the attempt of answering the question whether certain subclasses of HDL may be better predictors of cardiovascular risk than HDL cholesterol levels, and may be better targets than HDL cholesterol for further improving cardiovascular disease reduction in the statin era. How type 2 diabetes mellitus affects the expression and/or activity of receptors and proteins involved in HDL metabolism and how different diabetes-associated factors influence the functionality of HDL, is summarized in the review by Van Linthout et al. [5]. Furthermore, the review focuses on describing the newest insights in the impact of HDL on glucose metabolism and on diabetes-associated cardiovascular complications. The work by Spillmann et al. [6] gives an overview of current established HDL-raising pharmaca, including statins, fibrates, thiazolidinediones, and nicotinic acids, and of novel therapies, including cholesterol ester transfer protein-inhibitors, liver X receptor agonists, reconstituted HDL, and apolipoprotein A-I mimetics. Authors describe the underlying working mechanisms of the different drugs and discuss the results from clinical trials of monotherapy and combination therapy. They highlight the fact that the actual pharmacological agents (statins, fibrates, and nicotinic acids) used to treat dyslipidemia share the characteristic that their mechanism of action involve - be it in different gradations - a direct or indirect reduction in cholesterol ester transfer protein activity. This evidence base substantiates the argument that cholesterol ester transfer protein constitutes a preferential pharmacological target for HDL-raising therapies.

Accumulation of cholesterol by macrophages, leading to their transformation into foam cells is a key event in the initiation of atherosclerosis. As maintenance of cholesterol homeostasis in macrophages is essential to prevent foam cell formation, mechanisms by which macrophages export cellular cholesterol have been intensively investigated in recent years. Several epidemiological studies have shown that plasma levels of high-density lipoprotein (HDL) cholesterol are inversely correlated with the risk of atherosclerosis. The protective effect of HDL against macrophage foam cell formation and atherosclerosis is primarily attributed to its role in reverse cholesterol transport (RCT), a process by which excess cholesterol in peripheral tissues is transported to the liver for excretion. The present review discusses current knowledge on the biological activities of the major apolipoproteins, enzymes, lipid transfer proteins, receptors, and lipid transporters associated with HDL function and levels. In addition, current views on the molecular mechanisms underlying the atheroprotective functions of HDL beyond promotion of RCT, including the anti-oxidant, anti-thrombotic, anti-inflammatory and anti-apoptotic properties of HDL are summarized.

Atherosclerosis is the major cause of cardiovascular morbidity and mortality. A multitude of pro-atherogenic mediators are known liable for the initiation and progression of atherogenic vascular lesions. Only few endogenous molecules are known so far with cardiovascular protective properties, whereas high-density lipoprotein (HDL) is one of the most important. Beside cholesterol efflux, many pleiotropic cell-mediated functions of HDL are known so far. HDL is a spherical particle that contains different proteins and lipids. Especially sphingolipids, like sphingosine-1-phosphate (S1P), has gained great attention. The HDL associated S1P seems to be responsible for many of the pleiotropic effects of HDL by activating special S1P receptors. This review focuses on HDL associated sphingolipids as mediators of known protective pleiotropic effects of HDL and their possible therapeutic relevance.

Reduced levels of high-density lipoprotein cholesterol (HDL) are associated with a substantially increased risk of coronary disease and cardiovascular events. Furthermore, numerous studies have suggested that HDL may exert several potentially important antiatherosclerotic and endothelial-protective effects. In particular, the promotion of reverse cholesterol transport, i.e. cholesterol efflux from lipid-loaded macrophages in atherosclerotic lesions and the subsequent cholesterol transport back to the liver, has been proposed as an anti-atherogenic effect of HDL that may promote regression of atherosclerotic lesions. Moreover, endothelial dysfunction is thought to play a critical role in development and progression of atherosclerosis and several recent studies have suggested that HDL exerts direct endothelial-protective effects, such as stimulation of endothelial production of the anti-atherogenic molecule nitric oxide, anti-oxidant, anti-inflammatory and anti-thrombotic effects. Furthermore, it has been observed that HDL may stimulate endothelial repair processes, involving mobilisation and promotion of endothelial repair capacity of endothelial progenitor cells. The relative significance of these different potential anti-atherosclerotic effects of HDL remains still unclear at present. Importantly, at the same time it has been recognized that the vascular effects of HDL may be variable, i.e. the capacity of HDL to stimulate macrophage cholesterol efflux and endothelial-protective effects may be altered in patients with inflammatory or cardiovascular disease. The further characterisation of underlying mechanisms and the identification of the clinical relevance of this “HDL dysfunction” are currently an active field of research. HDL-targeted treatment strategies are at present intensely evaluated and may lead to increased HDL plasma levels and/or HDL-stimulated anti-atherosclerotic effects. The cardiovascular protection provided by such approaches may likely depend on HDL function or quality, i.e. the anti-atherosclerotic and endothelial-protective properties of the on-treatment HDL. Currently, several HDL-raising treatment strategies are examined in clinical trials, i.e. extended-release niacin, the CETP inhibitors dalcetrapib and anacetrapib, reconstituted forms of HDL (i.e. CSL-111) or apoA-I mimetics, and some of these are already in large clinical outcome studies on top of statin therapy to determine their efficacy and safety for cardiovascular prevention.

Plasma concentrations of HDL cholesterol (HDL-C) are strongly and inversely associated with cardiovascular risk, leading to the concept that therapies to enhance plasma HDL-C levels would be anti-atherogenic and protective against cardiovascular events. However, HDL are highly heterogeneous, with subclasses that can be separated and identified according to density, size, charge, and protein composition. There is evidence that these subclasses may differ in their functional anti-atherogenic properties. As a snapshot of the steady-state cholesterol carried by all HDL subclasses together, the individual HDL-C measurement is insufficient to capture the structural and functional variation in HDL particles. This review addresses the current knowledge on the structural and functional heterogeneity of HDL particles, and their relationship to cardiovascular disease, in the attempt of answering the question on whether certain subclasses of HDL may be better predictors of cardiovascular risk than HDL-C, and may be better targets than HDL-C for further improving cardiovascular disease reduction in the statin era.

Type 2 diabetes mellitus is associated with low high-density lipoprotein (HDL) cholesterol levels, which is an independent cardiovascular risk factor. Low HDL cholesterol concentrations reflect a dysregulation in HDL metabolism, which is determined by the concerted action of different proteins, including cholesterol ester transfer protein, lecithin: cholesterol acyltransferase, endothelial and lipoprotein lipase, phospholipid transfer protein, and hepatic lipase, as well as different receptors, including the scavenger receptor class B type I and ATP-binding cassette transporter A1 and G1. Type 2 diabetes mellitus is besides a dysregulation in HDL metabolism, also associated with dysfunctional HDL: HDL-mediated reverse cholesterol transport as well as the anti-oxidative and endothelial-protective features of HDL are impaired in type 2 diabetes mellitus. The first part of the present review gives an overview of how type 2 diabetes mellitus affects the expression and/or activity of receptors and proteins involved in HDL metabolism and how different diabetes-associated factors influence the functionality of HDL. The second part of the review focuses on describing the newest insights in the impact of HDL on glucose metabolism and on diabetes-associated cardiovascular complications.

Population studies have consistently shown that high-density lipoprotein (HDL) cholesterol levels are a strong, independent inverse predictor of cardiovascular disease. Every 1 mg/dl increase in HDL cholesterol is associated with a 2% to 3% decrease in coronary artery disease risk, independent of low-density lipoprotein (LDL) cholesterol and triglyceride levels. The primary mechanism for this protective effect is believed to be reverse cholesterol transport, but several other anti-inflammatory, anti-apoptotic, anti-oxidative functions for HDL have also been identified. Low HDL cholesterol is predictive of cardiovascular events in statin-treated patients with low LDL cholesterol, indicating that intensive lipid lowering strategies with statins alone are not sufficient to prevent cardiovascular events, and merging for additional effective HDL-raising therapy. This review focuses at giving an overview of current established HDLraising pharmaca, including statins, fibrates, thiazolidinediones, and nicotinic acids, and of novel therapies including cholesterol ester transfer protein-inhibitors, liver X receptor agonists, reconstituted HDL, and apolipoprotein A-I mimetics. Working mechanisms are described and results from clinical trials of monotherapy and combination therapy are discussed.

Plasma levels of high-density lipoprotein (HDL) cholesterol and its major apolipoprotein (apo), apo A-I, are inversely correlated with the incidence of ischemic cardiovascular diseases. Till now, evaluation of the hypothesis that elevation of HDL cholesterol reduces atherosclerotic burden and/or decreases ischemic cardiovascular events in humans has been hampered by the lack of drugs that selectively increase HDL cholesterol. In contrast to the lack of clinical data, evidence for a direct causal role of HDL in modulating atherogenesis in experimental models has been provided by investigations in human apo A-I transgenic mice and rabbits. The development of gene transfer technologies with a sufficiently high therapeutic index may pave the road for a selective and effective HDL raising therapeutic intervention. The goal of a therapeutic strategy that modulates HDL metabolism is not an increase of HDL cholesterol as such, but an enhancement of HDL function. The value of HDL cholesterol as a surrogate end-point to predict reduced atherosclerosis or a decrease in clinical events may be highly dependent on the mechanism leading to an increased level of HDL cholesterol. In the case of gene transfer, this implies that beneficial effects of increasing HDL cholesterol will be dependent on the transgene that is expressed. Here, we critically review HDL metabolism and HDL function in relation to the development of HDL raising gene transfer, advances and drawbacks of different gene transfer technologies, and experimental gene transfer studies evaluating the effect of raised HDL on histological and functional outcomes in animal models.