Open Access Research article

Treatment with apolipoprotein A-1 mimetic peptide reduces lupus-like manifestations in a murine lupus model of accelerated atherosclerosis

Jennifer MP Woo1, Zhuofeng Lin1, Mohamad Navab2, Casey Van Dyck1, Yvette Trejo-Lopez1, Krystal MT Woo1, Hongyun Li1, Lawrence W Castellani3, Xuping Wang3, Noriko Iikuni1, Ornella J Rullo4, Hui Wu1, Antonio La Cava1, Alan M Fogelman5, Aldons J Lusis2 and Betty P Tsao1*

Author Affiliations

1 Department of Medicine-Rheumatology, David Geffen School of Medicine, University of California, 1000 Veteran Avenue, Los Angeles, CA 90095, USA

2 Department of Medicine-Cardiology, David Geffen School of Medicine, University of California, 1000 Veteran Avenue, Los Angeles, CA 90095, USA

3 Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, David Geffen School of Medicine, University of California, 1000 Veteran Avenue, Los Angeles, CA 90095, USA

4 Department of Pediatrics-Rheumatology, David Geffen School of Medicine, University of California, 1000 Veteran Avenue, Los Angeles, CA 90095, USA

5 Department of Medicine, David Geffen School of Medicine, University of California, 1000 Veteran Avenue, Los Angeles, CA 90095, USA

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Arthritis Research & Therapy 2010, 12:R93  doi:10.1186/ar3020


See related editorial by Mendez-Fernandez and Major, http://arthritis-research.com/content/12/5/139

Published: 18 May 2010

Abstract

Introduction

The purpose of this study was to evaluate the effects of L-4F, an apolipoprotein A-1 mimetic peptide, alone or with pravastatin, in apoE-/-Fas-/-C57BL/6 mice that spontaneously develop immunoglobulin G (IgG) autoantibodies, glomerulonephritis, osteopenia, and atherosclerotic lesions on a normal chow diet.

Methods

Female mice, starting at eight to nine weeks of age, were treated for 27 weeks with 1) pravastatin, 2) L-4F, 3) L-4F plus pravastatin, or 4) vehicle control, followed by disease phenotype assessment.

Results

In preliminary studies, dysfunctional, proinflammatory high-density lipoproteins (piHDL) were decreased six hours after a single L-4F, but not scrambled L-4F, injection in eight- to nine-week old mice. After 35 weeks, L-4F-treated mice, in the absence/presence of pravastatin, had significantly smaller lymph nodes and glomerular tufts (PL, LP < 0.05), lower serum levels of IgG antibodies to double stranded DNA (dsDNA) (PL < 0.05) and oxidized phospholipids (oxPLs) (PL, LP < 0.005), and elevated total and vertebral bone mineral density (PL, LP < 0.01) compared to vehicle controls. Although all treatment groups presented larger aortic root lesions compared to vehicle controls, enlarged atheromas in combination treatment mice had significantly less infiltrated CD68+ macrophages (PLP < 0.01), significantly increased mean α-actin stained area (PLP < 0.05), and significantly lower levels of circulating markers for atherosclerosis progression, CCL19 (PL, LP < 0.0005) and VCAM-1 (PL < 0.0002).

Conclusions

L-4F treatment, alone or with pravastatin, significantly reduced IgG anti-dsDNA and IgG anti-oxPLs, proteinuria, glomerulonephritis, and osteopenia in a murine lupus model of accelerated atherosclerosis. Despite enlarged aortic lesions, increased smooth muscle content, decreased macrophage infiltration, and decreased pro-atherogenic chemokines in L-4F plus pravastatin treated mice suggest protective mechanisms not only on lupus-like disease, but also on potential plaque remodeling in a murine model of systemic lupus erythematosus (SLE) and accelerated atherosclerosis.