title: Treatment with apolipoprotein A-1 mimetic peptide reduces lupus-like manifestations in a murine lupus model of accelerated atherosclerosis.
abstract: 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.
authors.affiliation: Department of Medicine-Rheumatology, David Geffen School of Medicine, University of California, 1000 Veteran Avenue, Los Angeles, CA 90095, USA.
authors.forename: Jennifer M P
authors.initials: JM
authors.lastname: Woo
authors.forename: Zhuofeng
authors.initials: Z
authors.lastname: Lin
authors.forename: Mohamad
authors.initials: M
authors.lastname: Navab
authors.forename: Casey
authors.initials: C
authors.lastname: Van Dyck
authors.forename: Yvette
authors.initials: Y
authors.lastname: Trejo-Lopez
authors.forename: Krystal M T
authors.initials: KM
authors.lastname: Woo
authors.forename: Hongyun
authors.initials: H
authors.lastname: Li
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Castellani
authors.forename: Xuping
authors.initials: X
authors.lastname: Wang
authors.forename: Noriko
authors.initials: N
authors.lastname: Iikuni
authors.forename: Ornella J
authors.initials: OJ
authors.lastname: Rullo
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.forename: Antonio
authors.initials: A
authors.lastname: La Cava
authors.forename: Alan M
authors.initials: AM
authors.lastname: Fogelman
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.forename: Betty P
authors.initials: BP
authors.lastname: Tsao
mesh_terms: 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
chemical_list: 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