title: Ht31, a protein kinase A anchoring inhibitor, induces robust cholesterol efflux and reverses macrophage foam cell formation through ATP-binding cassette transporter A1.
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.
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.
authors.forename: Loretta
authors.initials: L
authors.lastname: Ma
authors.forename: Fumin
authors.initials: F
authors.lastname: Dong
authors.forename: Maxime
authors.initials: M
authors.lastname: Denis
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.forename: Ming-Dong
authors.initials: MD
authors.lastname: Wang
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zha
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology; D051379:Mice; D011506:Proteins / Q000494:pharmacology*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; C400224:Ht 31 protein, synthetic; D011506:Proteins; D002784:Cholesterol; D017868:Cyclic AMP-Dependent Protein Kinases