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Dysfunctional HDL and atherosclerotic cardiovascular disease
Robert S.Rosenson1, H.Bryan Brewer Jr2, Benjamin J.Ansell3, Philip Barter4, M.John Chapman5, Jay W.Heinecke6, Anatol Kontush5, Alan R.Tall7 and Nancy R.Webb8
Abstract | High-density lipoproteins (HDLs) protect against atherosclerosis by removing excess cholesterol from macrophages through the ATP-binding cassette transporterA1 (ABCA1) and ATP-binding cassette transporterG1 (ABCG1) pathways involved in reverse cholesterol transport. Factors that impair the availability of functional apolipoproteins or the activities of ABCA1 and ABCG1 could, therefore, strongly influence atherogenesis. HDL also inhibits lipid oxidation, restores endothelial function, exerts anti-inflammatory and antiapoptotic actions, and exerts anti-inflammatory actions in animal models. Such properties could contribute considerably to the capacity of HDL to inhibit atherosclerosis. Systemic and vascular inflammation has been proposed to convert HDL to a dysfunctional form that has impaired antiatherogenic effects. Aloss of anti-inflammatory and antioxidative proteins, perhaps in combination with a gain of proinflammatory proteins, might be another important component in rendering HDL dysfunctional. The proinflammatory enzyme myeloperoxidase induces both oxidative modification and nitrosylation of specific residues on plasma and arterial apolipoproteinA-I to render HDL dysfunctional, which results in impaired ABCA1 macrophage transport, the activation of inflammatory pathways, and an increased risk of coronary artery disease. Understandingthe features of dysfunctional HDL or apolipoproteinA-I in clinical practice might lead to new diagnostic and therapeutic approaches to atherosclerosis.
Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, USA.
Cardiovascular Research Institute, MedStar Research Institute, USA.
Cardiology Department, David Geffen School of Medicine at UCLA, USA.
Centre for Vascular Research at the University of New South Wales, Australia.
National Institute for Health andMedical Research at Piti-Salptrire University Hospital, France.
Division of Metabolism, Endocrinology and Nutrition, University ofWashington, USA.
Department ofMedicine, Columbia University, USA.
Pharmacology & Nutritional Sciences and Saha Cardiovascular Research Center, University of Kentucky College of Medicine, USA.
Correspondence to R.S.R. [email protected]
http://dx.doi.org/10.1038/nrcardio.2015.124
Web End =doi:10.1038/nrcardio.2015.124 Published online 1 Sep 2015
High-density lipoproteins (HDLs) confer protection against atherosclerosis in several ways and, consequently, low levels of HDL cholesterol (HDL-C) are present in many conditions that are associated with an increased risk of cardiovascular disease (CVD). Particles of HDL and/or its main protein constituent, apolipoproteinA-I (apoA-I), have diverse antiatherosclerotic influences1
that are determined by their physicochemical properties (FIG.1)2. The most established...