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

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 alpha-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.

• Authors: Jennifer M P Woo, Zhuofeng Lin, Mohamad Navab, Casey Van Dyck, Yvette Trejo-Lopez, Krystal M T Woo, Hongyun Li, Lawrence W Castellani, Xuping Wang, Noriko Iikuni, Ornella J Rullo, Hui Wu, Antonio La Cava, Alan M Fogelman, Aldons J Lusis, Betty P Tsao
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 12 Issue 3 Pg. R93 ( 2010) ISSN: 1478-6362 [Electronic] England
• PMID: 20482780 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoprotein A-I
• Apolipoproteins E
• Chemokines
• Cytokines
• Immunoglobulin G
• L-4F peptide
• Lipids
• Peptides
• fas Receptor
• Pravastatin

Topics

• Animals
• Apolipoprotein A-I (adverse effects, pharmacology, therapeutic use)
• Apolipoproteins E (genetics, metabolism)
• Bone Density (drug effects)
• Chemokines (blood)
• Cytokines (blood)
• Disease Models, Animal
• Female
• Immunoglobulin G (blood)
• Lipids (blood)
• Lupus Erythematosus, Systemic (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Peptides (adverse effects, pharmacology, therapeutic use)
• Plaque, Atherosclerotic (chemically induced, pathology)
• Pravastatin (adverse effects, pharmacology, therapeutic use)
• fas Receptor (genetics, metabolism)