Hsp27 promotes ABCA1 expression and cholesterol efflux through the PI3K/PKCζ/Sp1 pathway in THP-1 macrophages.

Heat shock protein 27 (Hsp27) is a putative biomarker and therapeutic target in atherosclerosis. This study was to explore the potential mechanisms underlying Hsp27 effects on ATP-binding cassette transporter A1 (ABCA1) expression and cellular cholesterol efflux. THP-1 macrophage-derived foam cells were infected with adenovirus to express wild-type Hsp27, hyper-phosphorylated Hsp27 mimic (3D Hsp27), antisense Hsp27 or hypo-phosphorylated Hsp27 mimic (3A Hsp27). Wild-type and 3D Hsp27 were found to up-regulate ABCA1 mRNA and protein expression and increase cholesterol efflux from cells. Expression of antisense or 3A Hsp27 suppressed the expression of ABCA1 and cholesterol efflux. Furthermore, over-expression of wild-type and 3D Hsp27 significantly increased the levels of phosphorylated specificity protein 1 (Sp1), protein kinase C ζ (PKCζ) and phosphatidylinositol 3-kinase (PI3K). In addition, the up-regulation of ABCA1 expression and cholesterol efflux induced by 3D Hsp27 was suppressed by inhibition of Sp1, PKCζ and PI3K with specific kinase inhibitors. Taken together, our results revealed that Hsp27 may up-regulate the expression of ABCA1 and promotes cholesterol efflux through activation of the PI3K/PKCζ/Sp1 signal pathway in THP-1 macrophage-derived foam cells. Our findings may partly explain the mechanisms underlying the anti-atherogenic effect of Hsp27.

Apelin-13 increases expression of ATP-binding cassette transporter A1 via activating protein kinase C α signaling in THP-1 macrophage-derived foam cells.

Apelin has an antiatherogenic function through activating protein kinase C (PKC) to initiate a series of cellular signaling pathways. PKC phosphorylates and stabilizes ATP-binding cassette transporter A1 (ABCA1) through inhibiting its degradation mediated by calpain. Thus, in the present study, we investigated whether apelin-13 affects expression of ABCA1 through PKC signaling. The results showed that apelin-13 dramatically increased cholesterol efflux from THP-1 macrophage-derived foam cells and reduced cellular cholesterol levels. ABCA1 protein but not mRNA levels were dramatically increased by apelin-13, and calpain-induced degradation of ABCA1 and calpain activity were suppressed with treatment of apelin-13. However, the effects of apelin-13 on ABCA1 protein expression, cellular cholesterol efflux and calpain activity were abolished by depletion of PKCα, suggesting the potential important role of PKCα. In addition, apelin-13 was shown to phosphorylate serine residues in ABCA1 through the PKCα pathway. Thus, apelin-13 appears to activate PKCα, phosphorylate ABCA1 and inhibit calpain-mediated proteolysis, thereby promoting cholesterol efflux and reducing foam cell formation. Our study herein described a possible mechanism for understanding the antiatherogenic effects of apelin on attenuating the progression of atherosclerosis.