High-density lipoproteins (HDLs) and their lipid and protein components, of which apolipoprotein AI (apo AI) is the principal protein by weight, continue to be the focus of intense interest as potential pharmacological targets for the prevention and treatment of disease. To date most of this effort has been directed towards stimulating their function in the transport of excess cholesterol from tissues (reverse cholesterol transport), and thereby preventing or reversing coronary atherosclerosis. Although great progress has been made in developing agents that raise HDL concentration and reverse lesion progression in animals, the outcomes of clinical trials of their effects on coronary heart disease in humans have been inconclusive. There is a consensus that further trials are warranted with existing agents, and that new agents need to be developed based on a better understanding of the metabolism of HDL and the biological properties of its components. It is also being increasingly recognised that HDL has therapeutic potential beyond atherosclerosis, related to multiple effects of the particles on endothelial receptors, lipid peroxidation, macrophage function, and bacterial endotoxins. Progress is also being made in the manipulation of HDL particles ex vivo to act as carriers for targeting drugs, genetic material, and vascular imaging agents to specific organs and cell types. Other investigators have focused on designing small peptides that mimic the biological activities of apo AI. Each of these areas holds great promise, but also raises many questions and challenges. This is an exciting and rapidly expanding area, involving researchers in many disciplines, in both academia and industry.
This Frontiers Research Topic will provide a timely overview of the field, the core of which will be composed of reviews of areas that have made rapid progress and look especially promising. It is expected that the range of subjects covered will prompt other researchers to submit original articles and commentaries that add to and complement these core contributions.
The first section will cover recent research advances in HDL composition, function and activities that are providing the foundations for new drug discovery. This includes the results of recent proteomic analyses; the molecular mechanisms of reverse cholesterol transport; the critical role of interstitial fluid HDLs and the lymphatic system in reverse cholesterol transport; the role of HDL-associated sphigosine-1-phosphate in endothelial function; and the anti-oxidant properties of different HDL components.
The second category of articles will focus on progress in preclinical research evaluating the therapeutic potential of different HDL-based interventions in animals, centred on (a) experimental models of atherosclerosis, ischemia-reperfusion injury, and endotoxin shock; (b) the potential for utilising reconstituted modified HDLs as delivery vehicles for drugs, genetic material, and contrast agents; and (c) progress in the development of apo AI mimetic peptides.
The third group of contributions will consider the current status of HDL targeted drugs that have reached the stage of clinical evaluation. Three strategies are being pursued clinically: cholesteryl ester transfer protein inhibition; infusion of reconstituted HDL preparations; and stimulation of apo AI synthesis in the liver.
The Topic will be the first collection of articles that encompasses the broad range of therapeutic potential of HDL, previous collections having focused on the anti-atherogenic properties of the particles.
High-density lipoproteins (HDLs) and their lipid and protein components, of which apolipoprotein AI (apo AI) is the principal protein by weight, continue to be the focus of intense interest as potential pharmacological targets for the prevention and treatment of disease. To date most of this effort has been directed towards stimulating their function in the transport of excess cholesterol from tissues (reverse cholesterol transport), and thereby preventing or reversing coronary atherosclerosis. Although great progress has been made in developing agents that raise HDL concentration and reverse lesion progression in animals, the outcomes of clinical trials of their effects on coronary heart disease in humans have been inconclusive. There is a consensus that further trials are warranted with existing agents, and that new agents need to be developed based on a better understanding of the metabolism of HDL and the biological properties of its components. It is also being increasingly recognised that HDL has therapeutic potential beyond atherosclerosis, related to multiple effects of the particles on endothelial receptors, lipid peroxidation, macrophage function, and bacterial endotoxins. Progress is also being made in the manipulation of HDL particles ex vivo to act as carriers for targeting drugs, genetic material, and vascular imaging agents to specific organs and cell types. Other investigators have focused on designing small peptides that mimic the biological activities of apo AI. Each of these areas holds great promise, but also raises many questions and challenges. This is an exciting and rapidly expanding area, involving researchers in many disciplines, in both academia and industry.
This Frontiers Research Topic will provide a timely overview of the field, the core of which will be composed of reviews of areas that have made rapid progress and look especially promising. It is expected that the range of subjects covered will prompt other researchers to submit original articles and commentaries that add to and complement these core contributions.
The first section will cover recent research advances in HDL composition, function and activities that are providing the foundations for new drug discovery. This includes the results of recent proteomic analyses; the molecular mechanisms of reverse cholesterol transport; the critical role of interstitial fluid HDLs and the lymphatic system in reverse cholesterol transport; the role of HDL-associated sphigosine-1-phosphate in endothelial function; and the anti-oxidant properties of different HDL components.
The second category of articles will focus on progress in preclinical research evaluating the therapeutic potential of different HDL-based interventions in animals, centred on (a) experimental models of atherosclerosis, ischemia-reperfusion injury, and endotoxin shock; (b) the potential for utilising reconstituted modified HDLs as delivery vehicles for drugs, genetic material, and contrast agents; and (c) progress in the development of apo AI mimetic peptides.
The third group of contributions will consider the current status of HDL targeted drugs that have reached the stage of clinical evaluation. Three strategies are being pursued clinically: cholesteryl ester transfer protein inhibition; infusion of reconstituted HDL preparations; and stimulation of apo AI synthesis in the liver.
The Topic will be the first collection of articles that encompasses the broad range of therapeutic potential of HDL, previous collections having focused on the anti-atherogenic properties of the particles.
