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

Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

NS Wade

Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

EK Wakeland

Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

AS Major

Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA amy.major{at}vanderbilt.edu

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.

Key Words: atherosclerosis • autoimmunity • high fat diet • lupus

Lupus, Vol. 17, No. 12, 1070-1078 (2008)
DOI: 10.1177/0961203308093551


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