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

被引：41

作者：

Woo, Jennifer M. P. ^{[1
,2
]}

Lin, Zhuofeng ^{[1
,2
]}

Navab, Mohamad

Van Dyck, Casey ^{[1
,2
]}

Trejo-Lopez, Yvette ^{[1
,2
]}

Woo, Krystal M. T. ^{[1
,2
]}

Li, Hongyun ^{[1
,2
]}

Castellani, Lawrence W. ^{[3
,4
,5
]}

Wang, Xuping ^{[3
,4
,5
]}

Iikuni, Noriko ^{[1
,2
]}

Rullo, Ornella J. ^{[6
]}

Wu, Hui ^{[1
,2
]}

La Cava, Antonio ^{[1
,2
]}

Fogelman, Alan M. ^{[3
]}

Lusis, Aldons J.

Tsao, Betty P. ^{[1
,2
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med Rheumatol, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med Cardiol, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[6] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat Rheumatol, Los Angeles, CA 90095 USA

来源：

ARTHRITIS RESEARCH & THERAPY | 2010年 / 12卷 / 03期

关键词：

HIGH-DENSITY-LIPOPROTEIN; E-NULL MICE; BONE-MINERAL DENSITY; ESTABLISHED ATHEROSCLEROSIS; AUTOIMMUNE-DISEASE; PLASMA-CHOLESTEROL; DEFICIENT MICE; KNOCKOUT MICE; CELL CONTENT; RISK-FACTORS;

D O I：

10.1186/ar3020

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 (P(L, LP) < 0.05), lower serum levels of IgG antibodies to double stranded DNA (dsDNA) (P(L) < 0.05) and oxidized phospholipids (oxPLs) (P(L, LP) < 0.005), and elevated total and vertebral bone mineral density (P(L, 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 (P(LP) < 0.01), significantly increased mean alpha- actin stained area (P(LP) < 0.05), and significantly lower levels of circulating markers for atherosclerosis progression, CCL19 (P(L, LP) < 0.0005) and VCAM-1 (P(L) < 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.

引用

页数：13

共 57 条

[1] Impaired clearance of apoptotic cells promotes synergy between atherogenesis and autoimmune disease [J].