Accelerated atherosclerosis is independent of feeding high fat diet in systemic lupus erythematosus-susceptible LDLr(-/-) mice - PubMed (original) (raw)

Accelerated atherosclerosis is independent of feeding high fat diet in systemic lupus erythematosus-susceptible LDLr(-/-) mice

N a Braun et al. Lupus. 2008 Dec.

Abstract

Individuals suffering from systemic lupus erythematosus (SLE) are predisposed to accelerate cardiovascular disease. Our laboratory has recently developed an animal model of SLE-accelerated atherosclerosis. We have shown that, following 8 weeks feeding high fat Western diet, radiation chimeras consisting of SLE-derived haematopoietic cells transferred to low-density lipoprotein (LDL)r(-/-) mice (LDLr.Sle) have increased atherosclerosis compared with C57Bl/6 bone marrow recipients (LDLr.B6). However, this feeding regimen resulted in significant mortality in SLE-susceptible mice compared with controls with surviving animals having extremely elevated serum cholesterol (>500 mg/dL) and increased serum markers of kidney pathology. To test the hypothesis that SLE-associated autoimmune dysregulation can exacerbate atherosclerosis under more mild serum cholesterol conditions (approximately 200 mg/dL), we examined SLE and lesion development in radiation chimeras fed either a normal chow or high fat Western diet for 8 weeks. High fat fed LDLr.Sle mice exhibited increased mortality and were significantly more hypertensive. LDLr.Sle mice had greater titres of antibodies against dsDNA, oxLDL and phospholipid compared with controls. Lupus-susceptibility increased the atherosclerotic lesions and the percentage of CD4(+) T cells in the lesions of proximal aortas, independent of diet. These data show that increased dyslipidemia resulting from high-fat feeding can exacerbate autoimmunity and associated vascular complications. Conversely, they also show that autoimmune dysregulation can accelerate atherosclerosis in LDLr-deficient animals independent of feeding high fat diet. Collectively this study provides additional evidence that the accelerated atherosclerosis observed in SLE is autoimmune associated.

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Figures

Figure 1. Severe dyslipidemia increases mortality and serum titres of dsDNA antibodies

(A) Percentage of mice (total of 9–13 mice per group) surviving following feeding chow diet (squares) or Western diet (circles) for 8 weeks. (B) Serum titres for anti-dsDNA antibodies in LDLr.B6 (solid symbols) and LDLr.Sle (open symbols) mice fed a chow or Western diet. (C) Body weights for LDLr.B6 (solid symbols) and LDLr.Sle (open symbols) mice fed a chow or Western diet. *P < 0.05 as determined by one-way ANOVA. Data represent two identical experiments.

Figure 2. Immune complex deposition, urine protein and blood pressure are increased in LDLr.Sle mice fed high fat diet

(A) LDLr.Sle mice fed high fat diet exhibit increased immune complex deposition in glomeruli as detected by immunohistochemistry. Shown is one representative mouse per group. Kidney sections from a total of five mice per group were analysed with similar results. (B) Urine protein grade in mice (3–7 mice per group) was determined by Chemstix at the time of killing. LDLr.Sle mice (open bars) have increase urine protein compared with LDLr.B6 controls (closed bars). (C) LDLr.Sle mice (open circles) on Western diet have increased systolic blood pressure compared with LDLr.Sle mice on chow diet (open squares) and LDLr.B6 mice fed chow (closed squares) or Western diet (closed circles). *P < 0.05 as determined by one-way ANOVA. Data represent two identical experiments.

Figure 3. Transfer of lupus-susceptibility to LDLr-deficient mice increases atherosclerosis independent of diet

(A) Average lesion area as determined by oil-red-O staining in LDLr.B6 (closed bars) and LDLr.Sle (open bars) mice. Lesion quantitation was performed on 9–11 mice in each group. Shown is data from two identical experiments. (B) Detection of CD4+ T cells in lesions of LDLr.B6 (closed bars) and LDLr.Sle (open bars) on chow or Western diet. Positive cells are expressed as a percent of all lesion cells as determined by DAPI staining. Four sections from 5–10 mice per group were analysed. (C) Primary CD4+ T cells were isolated from C57Bl/6 (B6) and B6._Sle_1.2.3 (Sle) mice and stimulated for 2 h with PMA and ionomycin. Shown is one of three experiments with similar results. *P < 0.05 as determined by Kruskal–Wallis test.

Figure 4. FPLC analyses of serum cholesterol lipoprotein distribution

Lipoproteins were separated by size-exclusion chromatography and assayed for cholesterol as described in ‘Methods’. Serum from LDLr.B6 (closed circles) and LDLr.Sle (open circles) was pooled before undergoing separation and analysis (9–11 mice per group). Similar profiles were obtained from individual mice.

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Accelerated atherosclerosis is independent of feeding high fat diet in systemic lupus erythematosus-susceptible LDLr(-/-) mice - PubMed (original) (raw)