ATP-binding cassette transporter A1 expression is decreased in preeclamptic placentas

Abstract

Preeclampsia is a pregnancy-specific multisystem disorder characterized by hypertension and proteinuria. Accentuated maternal hyperlipidemia, especially high serum levels of oxidized low-density lipoprotein (oxLDL), is one of the features of preeclampsia. We previously reported that lectin-like oxidized LDL receptor 1 (LOX-1) expression was decreased in preeclamptic placentas. Here, we show that decreased LOX-1 expression is associated with low expression of adenosine triphosphate-binding cassette transporter A1 (ABCA1) in the placenta. The ABCA1 mediates cellular efflux of cholesterol, and liver X receptors (LXRs) are its predominant transcriptional regulators. Both ABCA1 and LXR expressions were significantly lower in preeclamptic placentas than those in normal controls. Oxidized LDL upregulated ABCA1 expression, while LOX-1 blockade resulted in the alleviation of increasing ABCA1 messenger RNA in JAR cells. These results suggest that low LOX-1 expression may lead to insufficient oxLDL uptake, thereby contributing to reduced LXR activation and decreased ABCA1 expression in preeclamptic placentas.

Keywords: ABCA1; LOX-1; LXR; oxidized LDL; preeclampsia.

Figure 1.

Messenger RNA expressions of (A) ABCA1, and (B) LXRα and LXRβ in normal and preeclamptic placentas (n = 10 in each group). Values were normalized to those of GAPDH. Data are presented as the median value with interquartile range. *P < .05, **P < .01. ABCA1 indicates adenosine triphosphate-binding cassette transporter A1; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; LXR, liver X receptor.

Figure 2.

Expression of ABCA1 protein in normal and preeclamptic placentas (n = 10 in each group). A, Western blot for ABCA1 in placentas. B, Densitometric analysis of ABCA1 protein expression normalized to β-actin. Data are presented as the median value with interquartile range. * P < .05. ABCA1 indicates adenosine triphosphate-binding cassette transporter A1.

Figure 3.

The ABCA1 upregulation by oxLDL in JAR cells. A, Time courses of ABCA1 mRNA expression in JAR cells treated with oxLDL (100 µg/mL) or nLDL (100 µg/mL). B, A representative Western blot image for ABCA1 in JAR cells treated with or without oxLDL (100 µg/mL) for 9 hours. C, Time courses of LXRα and LXRβ mRNA expression in JAR cells treated with oxLDL (100 µg/mL). Values were normalized to those of GAPDH. Data are presented as the mean ± standard error of the mean. * P < .05, ** P < .01. Six experiments were performed in triplicate (n = 6). ABCA1 indicates adenosine triphosphate-binding cassette transporter A1; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; LXR, liver X receptor; mRNA, messenger RNA; nLDL, native low-density lipoprotein; oxLDL, oxidized low-density lipoprotein.

Figure 4.

Attenuation of increasing ABCA1 mRNA by LOX-1 blockade. ABCA1 mRNA expression in JAR cells treated with oxLDL (100 µg/mL) in the presence or absence of TS92 (30 µg/mL) or normal human IgG (30 µg/mL), and that in JAR cells treated with nLDL (100 µg/mL) for 9 hours. Values were normalized to those of GAPDH. Data are presented as the mean ± SEM. * P < .05, *** P < .001. Six experiments were performed in triplicate (n = 6). ABCA1 indicates adenosine triphosphate-binding cassette transporter A1; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; IgG, immunoglobulin G; LOX-1, lectin-like oxidized LDL receptor 1; mRNA, messenger RNA; nLDL, native low-density lipoprotein; oxLDL, oxidized low-density lipoprotein; SEM, standard error of the mean.

Figure 5.

Scheme of oxLDL-mediated signaling pathways in trophoblasts. The enhancement in ABCA1 expression following increased oxLDL is suppressed in preeclamptic placentas. ABCA1 indicates adenosine triphosphate-binding cassette transporter A1; oxLDL, oxidized low-density lipoprotein.