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Macrophage foam cell formation with native low density lipoprotein
Howard S Kruth1, Wei Huang, Itsuko Ishii
1Section of Experimental Atherosclerosis, NHLBI/National Institutes of Health, Bldg. 10 Rm. 5N-113, 10 Center Drive, MSC 1422, Bethesda, MD 20892, USA. kruthh@nhlbi.nih.gov
The Journal of Biological Chemistry
|July 16, 2002
Summary
Activated macrophages rapidly accumulate cholesterol via fluid phase endocytosis of native low-density lipoprotein (LDL), independent of LDL modification or receptors. This finding reveals a new mechanism for foam cell formation in atherosclerosis.
Area of Science:
- Cell Biology
- Biochemistry
- Cardiovascular Research
Background:
- Low-density lipoprotein (LDL) is implicated in cholesterol accumulation in macrophages within atherosclerotic plaques.
- Native LDL has not previously demonstrated significant cholesterol accumulation in macrophages.
- Understanding macrophage cholesterol metabolism is crucial for atherosclerosis research.
Purpose of the Study:
- To elucidate the mechanism of macrophage foam cell development induced by native LDL.
- To investigate the role of protein kinase C and LDL receptors in LDL uptake and cholesterol accumulation.
- To identify the pathway of LDL uptake in activated macrophages.
Main Methods:
- Activation of human monocyte-derived macrophages with phorbol 12-myristate 13-acetate (PMA).
- Quantification of intracellular cholesterol accumulation.
- Inhibition studies using protein kinase C inhibitors and anti-LDL receptor antibodies.
- Measurement of LDL uptake via fluid phase endocytosis using [(3)H]sucrose.
Main Results:
- PMA-activated macrophages exhibited massive cholesterol accumulation (>400 nmol/mg cell protein).
- Protein kinase C mediated PMA-stimulated LDL uptake; LDL receptors did not.
- LDL uptake occurred via fluid phase endocytosis, accounting for at least 83% of cholesterol delivery.
- Cholesterol accumulation was independent of LDL modification, antioxidants, or prior cholesterol enrichment.
Conclusions:
- Macrophage foam cell formation can occur without LDL modification through enhanced fluid phase endocytosis.
- PMA-stimulated macrophage activation drives significant LDL uptake and cholesterol esterification.
- Targeting macrophage fluid phase endocytosis presents a novel strategy for managing atherosclerosis.