Introduction
st-Ht31, a protein kinase A (PKA)-anchoring inhibitor, greatly induces robust cholesterol or phospholipid efflux from macrophage foam cells, providing an effective treatment against atherosclerosis. st-Ht31 completely reverses foam cell formation, which is improved by ATP-binding cassette transporter A1 (ABCA1). st-Ht31 effectively drives cholesterol out from the ATP-binding cassette transporter A1 expressing cells.
Pharmacologic action
st-Ht31 removes cholesterol out of the cell by increasing PKA activity specifically in the cytoplasm. Cholesterol efflux from peripheral cells is virtual to cholesterol homeostasis and normal cell function. ABCA1 is essential to cholesterol output. Disordered mutation of ABCA1 increases the risk of cardiovascular disease. ABCA1 is highly expressed in lipid-laden macrophages, accelerating the output of excess cholesterol. ABCA1 removes cholesterol depending upon PKA activity. st-Ht31, a membrane-permeable peptide for PKA de-anchoring, elevates cytosolic PKA activity and cholesterol efflux, maintaining normal cell function.
Functions
st-Ht31 is effective in reversing foam cell formation and regulating metabolic health of dysfunctional macrophages. Cells expressing ABCA1 release cholesterol, which blocked by PKA inhibitors. st-Ht31 is a stearated and membrane-permeable 24-residue peptide consisting of a PKA-anchoring domain. At the presence of st-Ht31, macrophages robustly release cholesterol. This kind of release by st-Ht31 predominantly happens in cells expressing ABCA1, with the st-Ht31 dose-dependent manner. st-Ht31 essentially induces the release of cholesterol efflux.
Pharmacokinetics and metabolism
The removal of excess cholesterol from macrophages is effective in preventing against atherosclerosis and cardiovascular disease. st-Ht31, a PKA anchoring inhibitor, stimulates robust cholesterol or phospholipid output, which is enhanced by ABCA1. At 50 μM st-Ht31, baby hamster kidney cells expressing ABCA1 output approximately 40% of cellular cholesterol within 2 hours. The effect of st-Ht31 is sharp, since the cholesterol output disappeared immediately when st-Ht31 was removed from the medium. st-Ht31 interferes with PKA anchoring behavior without directly affecting PKA catalytic capacity. st-Ht31 promotes cytosolic PKA activity by inhibiting PKA anchoring on PKA anchoring proteins (AKAPs). This behavior is significant for cholesterol efflux. There is no detectable toxicity related to st-Ht31, even if the cells output up to 20% of cellular cholesterol per hour.
References:
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Haidar B, Denis M, Marcil M, Krimbou L and Genest J. Apolipoprotein A-I Activates Cellular cAMP Signaling through the ABCA1 Transporter. J. Biol. Chem. 2004, 279, 9963–9969.
