Serum from SLE Patients Compromises Cholesterol Homeostasis in Cultured Human Aortic Endothelial Cells (HAEC) by Decreasing Cholesterol 27-Hydroxylase Expression

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Serum from SLE Patients Compromises Cholesterol Homeostasis in Cultured

Human Aortic Endothelial Cells (HAEC) by Decreasing Cholesterol

27-Hydroxylase Expression

Category:  Atherosclerosis

B Reiss1, Joan T Merrill2, Nguyen D Khoa1, Nahel W Awadallah1, Edwin

S L Chan1, Carmen Montesinos1, Bruce N Cronstein1

1NYU School of Medicine, New York, NY;2Oklahoma Medical Research Foundation,

Oklahoma City, OK

Presentation Number: 8

Keywords: Atherosclerosis, SLE, Complement

Background: Premature atherosclerotic cardiovascular disease (ASCVD) is a

common and devastating complication of SLE and it is likely that immunologic

derangements contribute to premature ASCVD in these patients. We have

recently reported that both immune complexes that have fixed C1q (IC-C1q)

and interferon-É¡ (immunologic reactants that play a role in the

pathogenesis of SLE) downregulate the enzyme cholesterol 27-hydroxylase in

human macrophages and human aortic endothelial cells (HAEC). This enzyme

catalyzes the first step in extrahepatic cholesterol metabolism and

generates signaling molecules (27-hydroxycholesterol) critical for

expression of ABCA1, a molecule involved in cholesterol efflux from

macrophages and which is defective in Tangier Disease (premature

atherosclerosis with normal serum lipids). We therefore determined whether

cholesterol 27-hydroxylase expression in cultured HAEC is modulated by serum

from SLE patients. Methods: HAEC (90% confluent), were incubated (3h, 370C,

5% C02) in medium containing either 50% normal human serum (NHS, n=12) or

50% serum from patients with SLE (n=36). Cellular mRNA was reverse

transcribed and the resulting cDNA subjected to PCR using 27-hydroxylase-

and GAPDH-specific primers. Results: 27-Hydroxylase message in HAEC

decreased by 51±5.5% after a 3h exposure to serum from SLE patients

(p<0.001). Serum from 70% of patients reduced expression of mRNA for

cholesterol 27-hydroxylase. Conclusion: Immune reactants in the serum of

patients with SLE may promote atherosclerosis by diminishing the expression

of 27-hydroxycholesterol in the vascular endothelium and macrophages of

patients with SLE and thereby induce a form of acquired Tangier Disease.