Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.

Effects of Apolipoprotein A-1 Mimetic Peptide in the Absence/Presence of Statin in a Murine Model of Accelerated Atherosclerosis in SLE

Woo¹, J. M.P., Lin¹, Z.F., Van Dyck¹, C., Trejo-Lopez¹, Y., Woo¹, K. M.T., Wang², X.P., Iikuni¹, N.

Division of Rheumatology, UCLA, Los Angeles, CA
Divisions of Microbiology, Immunology, and Molecular Genetics. Medicine, and Human Genetics. UCLA, Los Angeles, CA
Department of Pediatrics-Rheumatology, UCLA, Los Angeles, CA
Division of Cardiology, UCLA, Los Angeles, CA
Department of Medicine, UCLA, Los Angeles, CA

Purpose:

Evaluate the effects of an apolipoprotein A-1 mimetic peptide, L-4F, in the absence/presence of pravastatin in apoE^-/-Fas^-/-C57BL/6 mice, a murine model of accelerated atherosclerosis in SLE which spontaneously develops IgG autoantibodies, glomerulonephritis, and advanced atherosclerotic lesions on a normal chow diet.

Methods:

Female mice, starting at 8–9 weeks of age, were treated for 27 weeks with 1) pravastatin, 2) L-4F, 3) L-4F plus pravastatin, or 4) vehicle control. Following euthanasia, tissues were harvested for disease assessment. Tissue damage and systemic inflammation were determined via histology and immunohistochemical staining, circulating chemokine/cytokine and autoantibody levels, and DEXA and mCT analysis.

Results:

Only mice treated with L-4F in the absence/presence of pravastatin developed significantly smaller glomerular tufts (p_L,LP < 0.05), lower serum levels of IgG anti-dsDNA (p_L < 0.05) and anti-oxidized phospholipid (p_L,LP < 0.005) antibodies—with no significant difference in general immune suppression, elevated BMD (p_L,LP < 0.005), and lower proinflammatory plasma chemokine/cytokine levels (including CRP, CCL12, CCL19, and VCAM-1). Although all treatment groups presented 47–95% larger mean aortic root lesions, immunohistochemical staining showed a 37% decrease in mean infiltrated CD68 macrophages and a 59% increase in mean a-actin (smooth muscle) stained areas in aortic lesions of combination treatment mice compared to vehicle controls.

Conclusion:

Serological and histological analysis suggests that treatment with L-4F in the absence/presence of pravastatin significantly reduces systemic inflammation in our murine model with no significant difference between treatment with L-4F alone and the combination treatment. Compared to vehicle controls, treatment with L-4F plus pravastatin effectively reduced manifestations of lupus-like autoimmunity, glomerulonephritis, and osteopenia. In addition, cellular composition of atherosclerotic lesions was suggestive of plaque stabilization due to the increased smooth muscle tissue content and lower infiltrated CD68 macrophage population, despite larger lesion area, compared to vehicle controls.

Manifestation	Control^a (n = 23)	L-4F^a (n = 25)	p^b,^c	Pravastatin + L-4F^c (n = 9)	p^b,^c
Glomerular tuft size (mm²)	7,645 ± 1,200	6,845 ± 1,060	0.04	6,226 ± 1,007	0.004
IgG anti-dsDNA (AU)	132 ± 50	85 ± 43	0.007	120 ± 40	NS
IgG anti-oxidized phospholipid (AU)	29 ± 18	15 ± 9	0.002	9.3 ± .04	0.005
Total IgG (mg/ml)	4.5 ± 0.3	4.4 ± 0.7	NS	4.0 ± 0.7	NS
Lumbar BMD> (mg/cm²)	0.042 ± 0.007	0.051 ± 0.005	6 × 10^-6	0.053 ± 0.003	0.0002
Plasma cytokine/chemokines	(n = 16)	(n = 16)		(n = 8)
CRP	8.3 ± 2.2	6.2 ± 1.4	0.005	7.8 ± 1.5	NS
CCL12 (MCP-5)	201 ± 117	120 ± 70	0.03	110 ± 44	0.01
CCL19 (MIP-3b)	15 ± 7	5.5 ± 2.8	0.00004	5.3 ± 3.5	0.0001
VCAM-1	6221 ± 1600	3940 ± 1400	0.0002	4868 ± 1300	0.04
	(n = 5)	(n = 5)		(n = 4)
Aortic root lesion size (mm²)	0.19 ± 0.10	0.27 ± 0.13	0.019	0.37 ± 0.13	0.0003
CD68 stained area per lesion area (%)	9.8 ± 0.8	8.9 ± 2.0	NS	6.2 ± 1.2	0.006
a-actin stained area per lesion area (%)	4.9 ± 2.3	7.1 ± 1.0	0.08	7.8 ± 0.5	0.04
dsDNA, double-stranded DNA; BMD, bone mineral density
^a Values expressed as Mean ± SD
^bp-values taken in comparison to Control values and considered significant at p < 0.05
^c NS: not significant

To cite this abstract, please use the following information:
Woo, J. M.P., Lin, Z.F., Van Dyck, C., Trejo-Lopez, Y., Woo, K. M.T., Wang, X.P., et al; Effects of Apolipoprotein A-1 Mimetic Peptide in the Absence/Presence of Statin in a Murine Model of Accelerated Atherosclerosis in SLE [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1034
DOI: 10.1002/art.26111

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