D-4F, an apolipoprotein A-I mimetic peptide, promotes cholesterol efflux from macrophages via ATP-binding cassette transporter A1.
Cholesterol efflux is the key step of reverse cholesterol transport and has become a therapeutic target against atherosclerosis. Human apolipoprotein A-I (apoA-I) is the main protein in high-density lipoprotein (HDL) and has 243 amino acids. ApoA-I mimetic peptides have no sequence homology to apoA-I but possess the class-A amphipathic helical motif that presents in apoA-I lipid binding domains. D-4F is one of the apoA-I mimetic peptides and exerts diverse atheroprotective functions similar to apoA-I. However, the exact role of D-4F on lipid metabolism in macrophages is not clear yet. Therefore, we studied the effect of D-4F on cholesterol efflux, cAMP levels and expression of ATP-binding cassette transporter A1 (ABCA1) in RAW264.7 mouse macrophages. Cells were incubated with 1, 10, 50 or 100 microg/ml D-4F for 24 hours, and the cholesterol efflux was assessed. Here, D-4F significantly increased the cholesterol efflux in concentration- and time-dependent manners. Concomitantly, D-4F increased intracellular cAMP levels and the expression levels of ABCA1 mRNA and protein in a dose-dependent manner, consistent with the increase in the cholesterol efflux from macrophages. 8-Br-cAMP (cAMP activator) increased the D-4F-mediated cholesterol efflux by 39%. Moreover, the increases in cholesterol efflux and ABCA1 expression induced by 8-Br-cAMP could be inhibited by the treatment with H89, a protein kinase A (PKA) inhibitor. In conclusion, these results suggest that the synthetic peptide D-4F promotes cholesterol efflux in macrophages through the cAMP-PKA-ABCA1 pathway, which may open new avenues for the treatment of atherosclerosis.
Xie
Qiong
Q
Department of Cardiology, The Second Xiang Ya Hospital of Central South University, Changsha, Hunan, PR.
Zhao
Shui-ping
SP
Li
Feng
F
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000378:metabolism; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000494:pharmacology*; D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000378:metabolism
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; C465468:D-4F peptide; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D015124:8-Bromo Cyclic Adenosine Monophosphate; D002784:Cholesterol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide