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Antiatherogenic small, dense HDL—guardian angel of the arterial wall?

Abstract

Our understanding of the relationship between the atheroprotective activities of HDL and heterogeneity of HDL particles has advanced greatly. HDL particles are highly heterogeneous in structure, intravascular metabolism and antiatherogenic activity. In this review, we discuss new findings on the antiatherogenic properties of HDL particles. Small, dense HDL possesses potent antioxidative activity but this is compromised under conditions of atherogenic dyslipidemia. HDL functional deficiency frequently coincides with reductions in HDL-cholesterol concentration and alterations in HDL metabolism and structure. Formation of small, dense HDL particles with attenuated antiatherogenic activity can be mechanistically related to HDL enrichment in triglycerides and in serum amyloid A, depletion of cholesteryl esters, covalent modification of HDL apolipoproteins and attenuated antiatherogenic function of apolipoprotein AI. Low circulating levels of HDL cholesterol might, therefore, be associated with the defective functionality of small HDL particles of abnormal structure and composition. In common metabolic diseases, such as type 2 diabetes and metabolic syndrome, deficiency of HDL particle number and function favor accelerated atherosclerosis. Therapeutic normalization of the quantity, quality and biological activities of HDL particles thus represents a novel approach to attenuating atherosclerosis in dyslipidemic individuals with metabolic disease. Cholesteryl ester transfer protein inhibitors, nicotinic acid, reconstituted HDL and other HDL-raising agents are being investigated. Induction of selective increase in the circulating concentrations of small, dense HDL3 particles with increased antiatherogenic activity seems especially promising, particularly for therapy of atherogenic dyslipidemia.

Key Points

  • HDL particles are heterogeneous in structure, their effect on intravascular metabolism, and their antiatherogenic properties

  • Small, dense HDL (HDL3) possesses multiple antiatherogenic properties, including potent cholesterol efflux capacity and antioxidative, anti-inflammatory and antiapoptotic activities

  • The antiatherogenic activities of small, dense HDL3 are defective in the atherogenic dyslipidemic conditions, such as type 2 diabetes and metabolic syndrome, and frequently coincide with low HDL-cholesterol concentrations

  • Formation of functionally defective small, dense HDL in metabolic disease can be mechanistically related to elevated cholesteryl ester transfer protein activity and to attenuated antiatherogenic function of apolipoprotein AI

  • Deficiency of HDL particle numbers and function favors accelerated atherosclerosis

  • Cholesteryl ester transfer protein inhibitors, nicotinic acid, or reconstituted HDL or apolipoprotein AI mimetic peptides to normalize small, dense HDL3 concentration, composition and activities, represent novel antiatherosclerotic strategies in common metabolic diseases

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Figure 1: Heterogeneity, metabolism and biological activities of normal functional HDL (A) and of HDL with defective antiatherogenic function in the dyslipidemia of metabolic diseases (B).

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Acknowledgements

A Kontush was supported by INSERM, the International HDL Research Award from Pfizer, USA, Nouvelle Société Française d'Athérosclérose and Fondation pour la Recherche Médicale, France. MJ Chapman gratefully acknowledges the award of a Contrat d'Interface from Assistance Publique—Hôpitaux de Paris/INSERM and continuing support from INSERM and Nouvelle Société Française d'Athérosclérose, France.

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Correspondence to Anatol Kontush.

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Kontush, A., Chapman, M. Antiatherogenic small, dense HDL—guardian angel of the arterial wall?. Nat Rev Cardiol 3, 144–153 (2006). https://doi.org/10.1038/ncpcardio0500

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