Abstract
Background and Objectives: Atherosclerotic cardiovascular disease (CVD) remains a major cause of morbidity and mortality in persons with systemic lupus erythematosus (SLE, lupus). Atherosclerosis, which involves interplay between cholesterol metabolism and cellular inflammatory pathways, is primarily treated with statins since statins have lipid-lowering and anti-inflammatory properties. The Lupus Atherosclerosis Prevention Study (LAPS) was designed to investigate the efficacy of statins against CVD in SLE patients. LAPS demonstrated that 2 years of atorvastatin administration did not reduce atherosclerosis progression in lupus patients. In this LAPs substudy, we use cultured macrophages to explore the atherogenic properties of plasma from LAPS subjects to explain the mechanistic rationale for the inability of statins to reduce CVD in lupus. Materials and Methods: THP-1 differentiated macrophages were treated for 18 h with 10% SLE patient plasma obtained pre- and post-atorvastatin therapy or placebo. Gene expression of the following cholesterol transport genes was measured by qRT-PCR. For efflux—ATP binding cassette transporter (ABC)A1 and ABCG1, 27-hydroxylase, peroxisome proliferator-activated receptor (PPAR)γ, and liver X receptor (LXR)α; and for influx—cluster of differentiation 36 (CD36) and scavenger receptor (ScR)A1. Results: Macrophages exposed to plasma from both statin-treated and placebo-treated groups showed a significant decrease in cholesterol efflux proteins ATP binding cassette (ABC) transporters A1 and ABCG1, an increase in 27-hydroxylase, an increase in the LDL receptor and a decrease in intracellular free cholesterol. No change in influx receptors ScRA1 and CD36, nor nuclear proteins LXRα and PPARγ was observed. Conclusions: Statins do not normalize pro-atherogenic changes induced by lupus and these changes continue to worsen over time. This study provides mechanistic insight into LAPS findings by demonstrating that statins are overall ineffective in altering the balance of cholesterol transport gene expression in human macrophages. Furthermore, our study suggests that statins as a CVD treatment may not be useful in attenuating lipid overload in the SLE environment.
Highlights
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder associated with increased mortality
SLE plasma reduces 27-hydroxylase expression in human aortic endothelial cells by about 50% [12]. In this Lupus Atherosclerosis Prevention Study (LAPS) substudy, we examined the atherogenicity of lupus plasma obtained from study subjects before and after atorvastatin or placebo therapy
Atorvastatin-treated substudy participants’ clinical and immunological characteristics collected at entry were as follows: disease duration 0–22 years; 100% with presence of anti-ANA antibodies; 74% with presence of anti-dsDNA antibodies; 18% with presence of anti-Sm antibodies; 30% with anti-RNP
Summary
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder associated with increased mortality. The Lupus Atherosclerosis Prevention Study [8] (LAPS) was a randomized, double-blind, placebo-controlled trial of atorvastatin 40 mg versus matching placebo in 200 patients without clinical CVD enrolled from the Hopkins Lupus Cohort. LAPS demonstrated that 2 years of atorvastatin administration did not reduce atherosclerosis progression in lupus patients In this LAPs substudy, we use cultured macrophages to explore the atherogenic properties of plasma from LAPS subjects to explain the mechanistic rationale for the inability of statins to reduce CVD in lupus. Our study suggests that statins as a CVD treatment may not be useful in attenuating lipid overload in the SLE environment
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