Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis ANATOL KONTUSH AND M. JOHN CHAPMAN Dyslipoproteinemia and Atherosclerosis Research Unit, National Institute for Health and Medical Research, Ho ˆpital de la Pitie ´, Paris, France Abstract ............................................................................... 343 I. Introduction ............................................................................ 343 A. Inflammation and oxidative stress in the progression of atherosclerosis ................... 344 II. Functional high-density lipoprotein ....................................................... 345 A. Structure, composition, and heterogeneity.............................................. 345 B. Metabolism ......................................................................... 347 C. Biological activities .................................................................. 348 1. Cholesterol efflux capacity ......................................................... 348 2. Antioxidative activity ............................................................. 349 3. Anti-inflammatory activity......................................................... 351 4. Antiapoptotic, vasodilatory, antithrombotic, and anti-infectious activities ............... 351 III. Functionally defective high-density lipoprotein in dyslipidemic and inflammatory states ....... 352 A. Altered high-density lipoprotein composition and enzymatic activities in dyslipidemic and inflammatory states ................................................................. 352 1. Apolipoproteins ................................................................... 352 2. Enzymes with antioxidative and anti-inflammatory properties ........................ 354 3. Lipid components ................................................................. 354 B. Abnormal high-density lipoprotein metabolism in dyslipidemic and inflammatory states .... 355 C. Impaired high-density lipoprotein biological activities in dyslipidemic and inflammatory states .............................................................................. 356 1. Cholesterol efflux capacity ......................................................... 356 2. Antioxidative activity ............................................................. 358 3. Anti-inflammatory activity......................................................... 359 IV. Physiological relevance of defective high-density lipoprotein function in dyslipidemia and metabolic disease ....................................................................... 360 V. Functionally defective small, dense high-density lipoprotein as a therapeutic target ........... 361 A. Cholesteryl ester transfer protein inhibitors ............................................ 362 B. Niacin .............................................................................. 363 C. Fibrates ............................................................................ 364 D. Statins ............................................................................. 364 E. Reconstituted high-density lipoprotein ................................................. 365 F. Apolipoprotein-mimetic peptides ...................................................... 365 G. Combination therapy ................................................................ 366 VI. Conclusions ............................................................................ 366 Acknowledgments....................................................................... 366 References ............................................................................. 366 Address correspondence to: Dr. Anatol Kontush, INSERM Unite ´ 551, Pavillon Benjamin Delessert, Ho ˆpital de la Pitie ´, 83 boulevard de l’Ho ˆpital, 75651 Paris Cedex 13, France. E-mail: kontush@chups.jussieu.fr These studies were supported by the National Institute for Health and Medical Research (Institut National de la Sante ´ et de la Recherche Me ´dicale). A.K. was supported by the award of a Research Fellowship from Fondation pour la Recherche Me ´dicale (France), the French Atherosclerosis Society in partnership with AstraZeneca, and an International HDL Research Award from Pfizer (United States). Article, publication date, and citation information can be found at http://pharmrev.aspetjournals.org. doi:10.1124/pr.58.3.1. 0031-6997/06/5803-342–374$20.00 PHARMACOLOGICAL REVIEWS Vol. 58, No. 3 Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics 60301/3133396 Pharmacol Rev 58:342–374, 2006 Printed in U.S.A 342