Review Article | Published:

Dysfunctional HDL and atherosclerotic cardiovascular disease

Nature Reviews Cardiology volume 13, pages 4860 (2016) | Download Citation

Abstract

High-density lipoproteins (HDLs) protect against atherosclerosis by removing excess cholesterol from macrophages through the ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (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. A loss 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 apolipoprotein A-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. Understanding the features of dysfunctional HDL or apolipoprotein A-I in clinical practice might lead to new diagnostic and therapeutic approaches to atherosclerosis.

Key points

  • HDL protects against atherosclerosis through multiple mechanisms that include amelioration of endothelial dysfunction, removal of excess cholesterol from macrophages, and antioxidative, anti-inflammatory, and antiapoptotic effects

  • Under particular circumstances, HDL loses its atheroprotective properties, resulting in the formation of dysfunctional HDL particles

  • Dysfunctional HDL particles increase proinflammatory signalling and reduce the efflux of cholesterol from macrophages by the ATP-binding cassette transporter A1

  • In prospective studies, myeloperoxidase-mediated oxidation of particular residues on apolipoprotein A-I creates a dysfunctional HDL particle that is associated with an increased incidence of cardiovascular events

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Affiliations

  1. Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

    • Robert S. Rosenson
  2. Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, Washington, DC, USA.

    • H. Bryan Brewer Jr
  3. Cardiology Department, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

    • Benjamin J. Ansell
  4. Centre for Vascular Research at the University of New South Wales, Sydney, Australia.

    • Philip Barter
  5. National Institute for Health and Medical Research at Pitié-Salpétrière University Hospital, Paris, France.

    • M. John Chapman
  6. Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, USA.

    • Jay W. Heinecke
  7. INSERM-ICAN Research Unit 1166 of the National Institute for Health and Medical Research at Pitié-Salpétrière University Hospital, Paris, France.

    • Anatol Kontush
  8. Department of Medicine, Columbia University, New York, NY, USA.

    • Alan R. Tall
  9. Pharmacology & Nutritional Sciences and Saha Cardiovascular Research Center, University of Kentucky College of Medicine, Lexington, KY, USA.

    • Nancy R. Webb

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All the authors researched data for the article, substantially contributed to discussion of content, wrote the manuscript, and reviewed/edited it before submission.

Competing interests

R.S.R. has served as a member of advisory boards for Amgen, AstraZeneca, Eli Lilly, Genzyme, GlaxoSmithKline, Novartis, Regeneron, and Sanofi; received honoraria from Kowa, travel support from LipoScience, and royalties from UpToDate, Inc.; and participates in clinical trials sponsored by Amgen, AstraZeneca, and Sanofi. H.B.B. has served as a member of advisory boards for Amgen, AstraZeneca, CSL, Eli Lilly, Merck, Pifzer, and Roche; received honoraria from Amgen, AstraZeneca, CSL, Eli Lilly, Merck, Pfizer, and Roche; received travel support from Amgen, AstraZeneca, Eli Lilly, Merck, and Roche; participates in clinical trials sponsored by Eli Lilly and Roche; is a patent holder for HDL Therapeutics; and receives royalties from AstraZeneca. B.J.A. is a member of an advisory board for Amgen; receives honoraria from Kowa; and is a shareholder in Amgen and Bruin Pharma. P.B. is a member of advisory boards for AstraZeneca, CSL, Merck, Novartis, Pfizer, and Roche; has received honoraria form Abbott, AstraZeneca, Merck, Novartis, Pfizer, and Roche; and participates in clinical trials sponsored by AstraZeneca, Merck, Pfizer, and Roche. J.C. receives research funding from CSL, Kowa, and Pfizer; is a member of advisory boards for Amgen, CSL, Danone, Merck, and Sanofi-Regeneron; has received honoraria from Amgen, Danone, Merck, Sanofi-Regeneron, and Unilever; participates in a clinical trial sponsored by AstraZeneca; and is a patent holder on the use of negatively charged phospholipids to optimize the biological function of recombinant HDL. J.W.H. is a member of advisory boards for Amgen, Bristol Myers Squibb, GlaxoSmithKline, Insilicos, and Merck; and is a patent holder for the use of oxidation markers to predict the risk of cardiovascular disease. A.K. participates in a clinical trial sponsored by CSL; and is a patent holder for the use of negatively charged phospholipids to optimize the biological function of recombinant HDL. A.R.T. is a member of advisory boards for Amgen, Arisaph, CSL, Eli Lilly, and Pfizer. N.R.W. declares no competing interests.

Corresponding author

Correspondence to Robert S. Rosenson.

About this article

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DOI

https://doi.org/10.1038/nrcardio.2015.124

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