Tohoku J. Exp. Med., 2010, 220(3)

D-4F, an Apolipoprotein A-I Mimetic Peptide, Promotes Cholesterol Efflux from Macrophages via ATP-Binding Cassette Transporter A1

QIONG XIE,¹ SHUI-PING ZHAO¹ and FENG LI²

¹Department of Cardiology, The Second Xiang Ya Hospital of Central South University, Changsha, Hunan, P.R. China
²Department of Cardiothoracic Surgery, The Second Xiang Ya Hospital of Central South University, Changsha, Hunan, P.R. China

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 μg/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.

keywords —— apolipoprotein A-I mimetic peptide; cholesterol efflux; macrophage; cyclic AMP; ATP-binding cassette transporter A1

© 2010 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2010, 220, 223-228

Correspondence: Shui-Ping Zhao, Department of Cardiology, The Second Xiangya Hospital of Central South University, middle Ren-Min road No. 139, Changsha, Hunan 410011, P.R. China.

e-mail: zhaosp@medmail.com.cn, bestxq80@hotmail.com