Altered metabolism of LDL in the arterial wall precedes atherosclerosis regression.

Abstract

RATIONALE:

Plasma cholesterol lowering is beneficial in patients with atherosclerosis. However, it is unknown how it affects entry and degradation of low-density lipoprotein (LDL) particles in the lesioned arterial wall.

OBJECTIVE:

We studied the effect of lipid-lowering therapy on LDL permeability and degradation of LDL particles in atherosclerotic aortas of mice by measuring the accumulation of iodinated LDL particles in the arterial wall.

METHODS AND RESULTS:

Cholesterol-fed, LDL receptor-deficient mice were treated with either an anti-Apob antisense oligonucleotide or a mismatch control antisense oligonucleotide once a week for 1 or 4 weeks before injection with preparations of iodinated LDL particles. The anti-Apob antisense oligonucleotide reduced plasma cholesterol by ≈90%. The aortic LDL permeability and degradation rates of newly entered LDL particles were reduced by ≈50% and ≈85% already after 1 week of treatment despite an unchanged pool size of aortic iodinated LDL particles. In contrast, the size, foam cell content, and aortic pool size of iodinated LDL particles of aortic atherosclerotic plaques were not reduced until after 4 weeks of treatment with the anti-Apob antisense oligonucleotide.

CONCLUSIONS:

Improved endothelial barrier function toward the entry of plasma LDL particles and diminished aortic degradation of the newly entered LDL particles precede plaque regression.

• Authors: Emil D Bartels, Christina Christoffersen, Marie W Lindholm, Lars B Nielsen
• Journal: Circulation research (Circ Res) Vol. 117 Issue 11 Pg. 933-42 (Nov 06 2015) ISSN: 1524-4571 [Electronic] United States
• PMID: 26358193 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• Apob protein, mouse
• Apolipoprotein B-100
• Apolipoproteins B
• Cholesterol, Dietary
• Lipoproteins, LDL
• Oligonucleotides, Antisense
• Receptors, LDL

Topics

• Animals
• Aorta (metabolism, pathology)
• Aortic Diseases (genetics, metabolism, pathology, therapy)
• Apolipoprotein B-100
• Apolipoproteins B (genetics, metabolism)
• Atherosclerosis (genetics, metabolism, pathology, therapy)
• Capillary Permeability
• Cholesterol, Dietary (blood)
• Diet, High-Fat
• Disease Models, Animal
• Female
• Foam Cells (metabolism)
• Humans
• Lipoproteins, LDL (administration & dosage, blood, metabolism)
• Male
• Mice, Knockout
• Oligonucleotides, Antisense (administration & dosage, genetics, metabolism)
• Pinocytosis
• Plaque, Atherosclerotic
• Proteolysis
• Receptors, LDL (deficiency, genetics)
• Remission Induction
• Time Factors