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(Circulation. 2007;116:1832-1844.)
© 2007 American Heart Association, Inc.

Basic Science for Clinicians

Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis

Update and Therapeutic Implications

Ira Tabas, MD, PhD; Kevin Jon Williams, MD; Jan Borén, MD, PhD

From the Departments of Medicine, Pathology and Cell Biology, and of Physiology and Cellular Biophysics, Columbia University, New York, NY (I.T.); Dorrance H. Hamilton Research Laboratories, Division of Endocrinology, Diabetes, and Metabolic Diseases, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pa (K.J.W.); and the Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Gothenburg University, Gothenburg, Sweden (J.B.).

Correspondence to Ira Tabas, Department of Medicine, Columbia University Medical Center, 630 W 168th St, New York, NY 10032. E-mail iat1{at}columbia.edu

The key initiating process in atherogenesis is the subendothelial retention of apolipoprotein B–containing lipoproteins. Local biological responses to these retained lipoproteins, including a chronic and maladaptive macrophage- and T-cell–dominated inflammatory response, promote subsequent lesion development. The most effective therapy against atherothrombotic cardiovascular disease to date—low density lipoprotein–lowering drugs—is based on the principle that decreasing circulating apolipoprotein B lipoproteins decreases the probability that they will enter and be retained in the subendothelium. Ongoing improvements in this area include more aggressive lowering of low-density lipoprotein and other atherogenic lipoproteins in the plasma and initiation of low-density lipoprotein–lowering therapy at an earlier age in at-risk individuals. Potential future therapeutic approaches include attempts to block the interaction of apolipoprotein B lipoproteins with the specific subendothelial matrix molecules that mediate retention and to interfere with accessory molecules within the arterial wall that promote retention such as lipoprotein lipase, secretory sphingomyelinase, and secretory phospholipase A₂. Although not the primary focus of this review, therapeutic strategies that target the proatherogenic responses to retained lipoproteins and that promote the removal of atherogenic components of retained lipoproteins also hold promise. The finding that certain human populations of individuals who maintain lifelong low plasma levels of apolipoprotein B lipoproteins have an 90% decreased risk of coronary artery disease gives hope that our further understanding of the pathogenesis of this leading killer could lead to its eradication.

Key Words: atherosclerosis • cardiovascular diseases • extracellular matrix • lipoproteins • prevention • proteoglycans • statins

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