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Arthritis Res Ther. 2010; 12(3): R93.
Published online May 18, 2010. doi:  10.1186/ar3020
PMCID: PMC2911877
Treatment with apolipoprotein A-1 mimetic peptide reduces lupus-like manifestations in a murine lupus model of accelerated atherosclerosis
Jennifer MP Woo,1 Zhuofeng Lin,1 Mohamad Navab,2 Casey Van Dyck,1 Yvette Trejo-Lopez,1 Krystal MT Woo,1 Hongyun Li,1 Lawrence W Castellani,3 Xuping Wang,3 Noriko Iikuni,1 Ornella J Rullo,4 Hui Wu,1 Antonio La Cava,1 Alan M Fogelman,5 Aldons J Lusis,2 and Betty P Tsaocorresponding author1
1Department of Medicine-Rheumatology, David Geffen School of Medicine, University of California, 1000 Veteran Avenue, Los Angeles, CA 90095, USA
2Department of Medicine-Cardiology, David Geffen School of Medicine, University of California, 1000 Veteran Avenue, Los Angeles, CA 90095, USA
3Department 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
4Department of Pediatrics-Rheumatology, David Geffen School of Medicine, University of California, 1000 Veteran Avenue, Los Angeles, CA 90095, USA
5Department of Medicine, David Geffen School of Medicine, University of California, 1000 Veteran Avenue, Los Angeles, CA 90095, USA
corresponding authorCorresponding author.
Jennifer MP Woo: jenwoo/at/ucla.edu; Zhuofeng Lin: zflwf/at/yahoo.com.cn; Mohamad Navab: MNavab/at/mednet.ucla.edu; Casey Van Dyck: CVanDyck/at/college.ucla.edu; Yvette Trejo-Lopez: YTrejo/at/mednet.ucla.edu; Krystal MT Woo: kryswoo/at/gmail.com; Hongyun Li: Hongyun.hyli/at/gmail.com; Lawrence W Castellani: LCastellani/at/mednet.ucla.edu; Xuping Wang: xpwang/at/mednet.ucla.edu; Noriko Iikuni: iikuni_noriko/at/lilly.com; Ornella J Rullo: orullo/at/mednet.ucla.edu; Hui Wu: huiwu2005/at/gmail.com; Antonio La Cava: ALaCava/at/mednet.ucla.edu; Alan M Fogelman: AFogelman/at/mednet.ucla.edu; Aldons J Lusis: JLusis/at/mednet.ucla.edu; Betty P Tsao: BTsao/at/mednet.ucla.edu
Received January 26, 2010; Revised April 26, 2010; Accepted May 18, 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.
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