Abstract
BackgroundBased on studies that date back to the 1920s, regression and stabilization of atherosclerosis in humans has gone from just a dream to one that is achievable. Review of the literature indicates that the successful attempts at regression generally applied robust measures to improve plasma lipoprotein profiles. Examples include extensive lowering of plasma concentrations of atherogenic apolipoprotein B and enhancement of reverse cholesterol transport from atheromata to the liver. FindingsPossible mechanisms responsible for lesion shrinkage include decreased retention of atherogenic apolipoprotein B within the arterial wall, efflux of cholesterol and other toxic lipids from plaques, emigration of lesional foam cells out of the arterial wall, and influx of healthy phagocytes that remove necrotic debris as well as other components of the plaque. This review will highlight the role key players such as LXR, HDL and CCR7 have in mediating regression. ConclusionAlthough much progress has been made, there are many unanswered questions. There is, therefore, a clear need for preclinical and clinical testing of new agents expected to facilitate atherosclerosis regression with the hope that additional mechanistic insights will allow further progress.
Highlights
Atherosclerosis, a chronic inflammatory disease that occurs within the artery wall, is one of the underlying causes of vascular complications such as myocardial infarction, stroke, and peripheral vascular disease
The monocytes roll along the endothelial cells via interactions of specific selectins, [i.e., P-selectin glycoprotein ligand-1 (PSGL-1)] with attachment being mediated by monocyte integrins such as very late antigen-4 (VLA-4) and lymphocyte function-associated antigen 1 (LFA-1) to the respective endothelial ligands vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1)
The crucial event in atherosclerosis initiation is the retention, or trapping, of apolipoproteinB-containing lipoproteins within the arterial wall; this process leads to local responses to this retained material, including a maladaptive infiltrate of macrophages that consume the retained lipoproteins but fail to emigrate
Summary
Atherosclerosis, a chronic inflammatory disease that occurs within the artery wall, is one of the underlying causes of vascular complications such as myocardial infarction, stroke, and peripheral vascular disease. Injection of LDLR−/− mice that had developed fatty streak lesions after a 5-week WD, with an adenoviral vector containing cDNA encoding human apoA-I caused a significant increase in HDL-cholesterol level and, importantly, regression of fatty streak lesions at a sampling point four weeks later.[36] The ability of HDL-like particles to rapidly remodel plaques in mice was shown by infusion of apoA-IMilano/PC complexes, a variant of apolipoprotein A–I identified in individuals who exhibit very low HDL cholesterol levels Infusion of this complex reduced foam cell content in arterial lesions in apoE−/− mice within 48 hours.[37] This finding was corroborated by a specific transplantation model that we reported in 2001,38 described later. These findings were attributed in part to the entry of expressed apoE into the vessel wall, consistent with other studies;[47,48,49,50] another plausible mechanism is that expressed apoE might have improved clearance of atherogenic lipoproteins in the postprandial state
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