Contribution of D4-F to ABCA1 expression and cholesterol efflux in THP-1 macrophage-derived foam cells.
Adenosine triphosphate-binding cassette transporter A1 (ABCA1) plays a crucial role in apolipoprotein A-I (apoA-I) binding activity and promotes cellular cholesterol efflux. ApoA-I mimetic peptide D4-F has reported to have the similar ability as apoA-I. However, the detailed mechanisms of ABCA1 regulation by D4-F are not understood. In the present study, we investigated the effects of D4-F on ABCA1 expression and ABCA1-dependent cholesterol efflux and examined the role of Cdc42/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway on the regulation of ABCA1 by D4-F in THP-1 macrophage-derived foam cells. Results showed that D4-F stabilized ABCA1 protein and enhanced ABCA1-dependent cholesterol efflux but had no effect on ABCA1 messenger RNA expression. We also revealed that D4-F enhanced cAMP level and PKA activity and ABCA1 serine phosphorylation. Short interfering RNA of PKA led to reduction of ABCA1 serine phosphorylation and ABCA1-mediated cholesterol efflux compensated by D4-F. PKA-specific activation by PKA agonist enhanced the upregulation of ABCA1 serine phosphorylation and ABCA1-mediated cholesterol efflux by D4-F. However, ABCA1 expression did not change by treatment with PKA agonist or PKA-short interfering RNA. We found that secramine B of Cdc42 inhibitor reduced the cAMP level compensated by D4-F. These results provide evidence that D4-F enhances ABCA1 serine phosphorylation and ABCA1-dependent cholesterol efflux through Cdc42/cAMP/PKA pathway in THP-1 macrophage-derived foam cells.
Liu
Xie-Hong
XH
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hengyang, China.
Xiao
Ji
J
Mo
Zhong-Cheng
ZC
Yin
Kai
K
Jiang
Jin
J
Cui
Li-Bao
LB
Tan
Chun-Zhi
CZ
Tang
Ya-Ling
YL
Liao
Duan-Fang
DF
Tang
Chao-Ke
CK
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D016632:Apolipoprotein A-I / Q000494:pharmacology*; D001692:Biological Transport; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation; D020764:cdc42 GTP-Binding Protein / 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; D012333:RNA, Messenger; D012694:Serine; D002784:Cholesterol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020764:cdc42 GTP-Binding Protein