Ht31, a Protein Kinase A Anchoring Inhibitor, Induces Robust Cholesterol Efflux and Reverses Macrophage Foam Cell Formation through ATP-binding Cassette Transporter A1

• Published in: The Journal of biological chemistry Vol. 286; no. 5; pp. 3370 - 3378
• Main Authors: Ma, Loretta, Dong, Fumin, Denis, Maxime, Feng, Ying, Wang, Ming-Dong, Zha, Xiaohui
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.02.2011; American Society for Biochemistry and Molecular Biology
• Subjects: A-Kinase Anchoring Protein; ABC Transporter; ABCA1; ABCA1 protein; Animals; Arteriosclerosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - physiology; ATP-binding protein; Biological Transport - drug effects; Biosensors; Cell Line; Cholesterol; Cholesterol - metabolism; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cytoplasm; fluorescence resonance energy transfer; Fluorescence Resonance Energy Transfer (FRET); Foam Cells - cytology; Foam Cells - drug effects; Inflammation; Lipids; Lipopolysaccharides; Macrophage; Macrophages; Macrophages - cytology; Mice; Phospholipids; Protein kinase A; Protein Kinase A (PKA); Proteins - pharmacology; Toxicity; ABCA1; Protein Kinase A (PKA); ABC Transporter; Fluorescence Resonance Energy Transfer (FRET); Cholesterol; A-Kinase Anchoring Protein; Macrophage
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.173666

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.