oa Editorial [Hot topic:The Two Faces of High-Density Lipoprotein (Executive Editor: Sophie Van Linthout)

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.