Altered Metabolism of LDL in the Arterial Wall Precedes Atherosclerosis Regression
Rationale: Plasma cholesterol lowering is beneficial in patients with atherosclerosis. However, it is unknown how it affects entry and degradation of LDL in the lesioned arterial wall.
Objective: We studied the effect of lipid-lowering therapy on LDL permeability and degradation of LDL in atherosclerotic aortas of mice by measuring the accumulation of iodinated LDL in the arterial wall.
Methods and Results: Cholesterol-fed, LDL-receptor deficient mice were treated with either an Apob antisense oligonucleotide (anti-Apob ASO) or a mismatch control ASO once a week for 1 or 4 weeks before injection with preparations of iodinated LDL. The anti-Apob ASO reduced plasma cholesterol by ~90%. The Aortic LDL permeability and degradation rates of newly entered LDL were reduced by ~50% and ~85% already after 1 week of treatment despite an unchanged pool size of aortic iodinated LDL. In contrast, the size, foam cell content, and aortic pool size of iodinated LDL of aortic atherosclerotic plaques were not reduced until after 4 weeks of treatment with the anti-Apob ASO.
Conclusions: Improved endothelial barrier function towards entry of plasma LDL and diminished aortic degradation of the newly entered LDL precede plaque regression.
- Arterial LDL permeability
- Arterial LDL degradation
- cholesterol-lowering drugs
- Received July 9, 2015.
- Revision received September 7, 2015.
- Accepted September 10, 2015.