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Ht31, a Protein Kinase A Anchoring Inhibitor, Induces Robust Cholesterol Efflux and Reverses Macrophage Foam Cell Formation through ATP-binding Cassette Transporter A1
- Source :
- Journal of Biological Chemistry. 286:3370-3378
- Publication Year :
- 2011
- Publisher :
- Elsevier BV, 2011.
-
Abstract
- Macrophage foam cell is the predominant cell type in atherosclerotic lesions. Removal of excess cholesterol from macrophages thus offers effective protection against atherosclerosis. Here we report that a protein kinase A (PKA)-anchoring inhibitor, st-Ht31, induces robust cholesterol/phospholipid efflux, and ATP-binding cassette transporter A1 (ABCA1) greatly facilitates this process. Remarkably, we found that st-Ht31 completely reverses foam cell formation, and this process is ABCA1-dependent. The reversal is also accompanied by the restoration of well modulated inflammatory response to LPS. There is no detectable toxicity associated with st-Ht31, even when cells export up to 20% cellular cholesterol per hour. Using FRET-based PKA biosensors in live cells, we provide evidence that st-Ht31 drives cholesterol efflux by elevating PKA activity specifically in the cytoplasm. Furthermore, ABCA1 facilitates st-Ht31 uptake. This allows st-Ht31 to effectively remove cholesterol from ABCA1-expressing cells. We speculate that de-anchoring of PKA offers a novel therapeutic strategy to remove excess cholesterol from lipid-laden lesion macrophages.
- Subjects :
- Phospholipid efflux
ATP-binding cassette transporter
Biochemistry
Cell Line
Mice
Animals
Molecular Biology
Foam cell
biology
Kinase
Macrophages
Proteins
Biological Transport
Cell Biology
Lipids
Cyclic AMP-Dependent Protein Kinases
Cell biology
Cholesterol
ATP Binding Cassette Transporter 1
Cytoplasm
Cell culture
ABCA1
biology.protein
ATP-Binding Cassette Transporters
lipids (amino acids, peptides, and proteins)
Foam Cells
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 286
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....b6d2efadb01e02005bc9353294525aa6