Treatment with apolipoprotein A-1 mimetic peptide reduces lupus-like manifestations in a murine lupus model of accelerated atherosclerosis.
BACKGROUND
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.
Woo
Jennifer M P
JM
Department of Medicine-Rheumatology, David Geffen School of Medicine, University of California, 1000 Veteran Avenue, Los Angeles, CA 90095, USA.
Lin
Zhuofeng
Z
Navab
Mohamad
M
Van Dyck
Casey
C
Trejo-Lopez
Yvette
Y
Woo
Krystal M T
KM
Li
Hongyun
H
Castellani
Lawrence W
LW
Wang
Xuping
X
Iikuni
Noriko
N
Rullo
Ornella J
OJ
Wu
Hui
H
La Cava
Antonio
A
Fogelman
Alan M
AM
Lusis
Aldons J
AJ
Tsao
Betty P
BP
D000818:Animals; D016632:Apolipoprotein A-I / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D008055:Lipids / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D058226:Plaque, Atherosclerotic / Q000139:chemically induced / Q000473:pathology; D017035:Pravastatin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D018925:Chemokines; D016207:Cytokines; D007074:Immunoglobulin G; C472885:L-4F peptide; D008055:Lipids; D010455:Peptides; D019014:fas Receptor; D017035:Pravastatin