Lack of association between circulating levels of oxidized LDL/ β 2-glycoprotein I complexes and leukocyte ABCA1 gene expression

ATP binding cassette A1 (ABCA1) is a key participant in the reverse cholesterol transport whereby it mediates cholesterol efflux directly to HDL particles. The experimental observation that oxidized LDL (oxLDL) can act as a modulator of leukocyte ABCA1 gene expression ¹ suggests that oxidative stress may have a significant impact in the clinical setting. To test this possibility we have examined the associations of oxLDL/β2-glycoprotein I (β2GPI) complex concentration with the ABCA1 expression in leukocytes in a group of 60 apparently healthy women (54.7 ± 4.6 y of age, body mass index 25.2 ± 1.6 kg/m²). Blood monocytes are precursors of macrophages, that are key elements of atherosclerotic plaque, and regulation of ABCA1 expression in leukocytes may partially reflect that in macrophages. ²

Leukocyte mRNA expression of ABCA1 was quantified using realtime polymerase chain reaction. The total serum antioxidant capacity (TAC) was measured as ferric reducing ability of plasma and the serum levels of oxLDL/β2GPI complexes were determined by enzyme-linked immunosorbent assay. Approval for this study was given by the local ethics committee, and informed consent was obtained from all patients. Details of the study design and laboratory measurements have been reported earlier. ^3,4

Study participants had a median oxLDL/β2GPI complex level of 8.53 U/mL (range, 1.24–19.09 U/mL). The correlations linking ABCA1 with oxLDL/β2GPI complex (P = 0.45), TAC (P = 0.36) and HDL (P = 0.15) were all non-significant. We divided participants into two equal size groups of high and low oxLDL/β2GPI complex values. The chosen cut-off point corresponds to the round number closest to the median value for the measure. Serum triglyceride was significantly higher in the group with elevated oxLDL/β2GPI values than in the other group (P = 0.007), which may be important to understand the relation of oxidative stress with dyslipidemia and cardiovascular disease. The two groups did not differ with respect to leukocyte ABCA1 gene levels (Table 1) even after adjustment for TAC. Similarly, after adjustment for ABCA1 expression, the relationship between oxLDL/β2GPI and TAC remained non-significant.

Table 1

Subject characteristics according to oxidized LDL/β2-glycoprotein I (oxLDL/β2GPI) complexes levels*

	Group 1 oxLDL/β2GPI <9 U/mL (n = 30)	Group 2 oxLDL/β2GPI ≥9 U/mL (n = 30)	P
Age (y)	54.9 ± 4.5	54.5 ± 4.8	0.70
Body mass index (kg/m2)	25.2 ± 1.7	25.2 ± 1.5	0.90
Cholesterol (mmol/L)	5.08 ± 1.01	5.41 ± 1.06	0.18
Triglyceride (mmol/L)	1.45 ± 0.44	1.89 ± 0.62	0.01
HDL cholesterol (mmol/L)	1.22 ± 0.31	1.11 ± 0.26	0.19
LDL cholesterol (mmol/L)	3.11 ± 0.67	3.31 ± 0.72	0.23
ApoA-I (g/L)	1.47 ± 0.19	1.47 ± 0.18	0.98
ApoB (g/L)	1.12 ± 0.20	1.22 ± 0.24	0.06
Log triglyceride/HDL cholesterol	0.43 ± 0.19	0.58 ± 0.18	0.01
TAC (mmol/L)	0.52 (0.37–0.95)	0.50 (0.32–0.79)	0.76
ABCA1, fold	1.12 (0.29–3.31)	1.06 (0.26–2.49)	0.34

ABCA1, ATP binding cassette A1; ApoA-1, apolipoprotein A-1; ApoB, apolipoprotein B; TAC, total serum antioxidant capacity

*Values are means ± SD or, if variables did not exhibit normal distribution, medians with ranges in brackets

These data demonstrate the lack of any significant association between ABCA1 expression and increased levels of oxLDL/β2GPI, serving as an integrative marker for systemic oxidative stress. ⁵ Moreover, the association of ABCA1 expression with oxLDL/β2GPI remained non-significant even after adjustment for TAC, which is known to be an important metabolic indicator of the overall antioxidant status. Xu et al. ⁶ found that leukocyte expression of ABCA1 is reduced in hypertensive patients and associated with the impairment of cholesterol efflux from macrophages. Given that the association between dyslipidemia and arterial hypertension is thought to be mainly due to an oxLDL-induced endothelial dysfunction, ⁷ there may be a complex interaction between lipid profile and oxidation status on ABCA1 gene expression. Despite the association between oxLDL/β2GPI levels and unfavourable lipid profile, our data did not support the hypothesis that the oxidative stress is associated with ABCA1 gene expression in healthy postmenopausal women. Furthermore, the high oxLDL/β2GPI levels were not attributable to impaired antioxidant status.

DECLARATIONS

Competing interests: Not applicable.

Funding: This research was funded by the Isfahan University of Medical Sciences (grant no. 388149).

Ethical approval: The ethics committee of the Isfahan University of Medical Sciences approved this study (388149).

Guarantor: MP.

Contributorship: MD researched literature, conceived the study and wrote manuscript. MD, AM and EZ were involved in protocol develeopment, patient recruitment and data analysis. All authors reviewed and approved the manuscript.