Abstract
Aims:
Plasma concentrations of high-density lipoprotein (HDL)-cholesterol correlate inversely with the incidence of myocardial infarction in humans. We investigated the effect of treatment with human apolipoprotein A-I (apoA-I), the principal protein of HDL, on plaque disruption in an animal model.
Methods and results:
Seventy apolipoprotein E knockout mice were induced to develop atherosclerotic lesions in the brachiocephalic artery by feeding a high-fat diet for 9 weeks. Mice then received twice-weekly treatment with human apoA-I (8 mg/kg) or vehicle, for 2 weeks. The incidence of acute plaque disruption was reduced by 65% in mice receiving apoA-I (P < 0.01). Plaques in treated mice had a more stable phenotype, with an increase in smooth muscle cell (SMC): macrophage ratio (P = 0.05), principally the consequence of an increase in the number of SMC in plaques. In the fibrous cap, there were reductions in matrix metalloproteinase-13 (-69%, P < 0.0001) and S100A4, a marker of SMC de-differentiation (-60%, P < 0.0001). These results indicate that 2 weeks of treatment with small amounts of human apoA-I produces more stable plaques in a mouse model.
Conclusion:
Treatment with apoA-I has the potential to stabilize plaques and prevent plaque rupture in humans.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apolipoprotein A-I / administration & dosage*
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Apolipoproteins E / deficiency
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Apolipoproteins E / genetics
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Atherosclerosis / blood
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Atherosclerosis / drug therapy*
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Atherosclerosis / genetics
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Atherosclerosis / pathology
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Brachiocephalic Trunk / drug effects*
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Brachiocephalic Trunk / metabolism
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Brachiocephalic Trunk / pathology
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Cardiovascular Agents / administration & dosage*
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Cell Dedifferentiation
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Cholesterol, HDL / blood
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Collagen / metabolism
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Disease Models, Animal
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Fibrosis
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Humans
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Inflammation Mediators / metabolism
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Macrophages / drug effects
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Macrophages / pathology
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Male
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Matrix Metalloproteinase 13 / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / pathology
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Myocytes, Smooth Muscle / drug effects
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Myocytes, Smooth Muscle / pathology
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Plaque, Atherosclerotic / blood
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Plaque, Atherosclerotic / drug therapy*
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Plaque, Atherosclerotic / genetics
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Plaque, Atherosclerotic / pathology
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Rupture, Spontaneous
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S100 Calcium-Binding Protein A4
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S100 Proteins / metabolism
Substances
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APOA1 protein, human
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Apolipoprotein A-I
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Apolipoproteins E
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Cardiovascular Agents
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Cholesterol, HDL
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Inflammation Mediators
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S100 Calcium-Binding Protein A4
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S100 Proteins
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S100a4 protein, mouse
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Collagen
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Matrix Metalloproteinase 13
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Mmp13 protein, mouse