Accelerated atherosclerosis is independent of feeding high fat diet in systemic lupus erythematosus-susceptible LDLr(-/-) mice.
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.
Braun
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Na
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6300, USA.
Wade
N S
NS
Wakeland
E K
EK
Major
A S
AS
D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000378:metabolism; D050197:Atherosclerosis / Q000150:complications / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D008078:Cholesterol, LDL / Q000378:metabolism; D015243:Cholesterol, VLDL / Q000378:metabolism; D004247:DNA / Q000276:immunology; D004041:Dietary Fats / Q000494:pharmacology*; D050171:Dyslipidemias / Q000150:complications / Q000235:genetics / Q000276:immunology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism
D017152:Antibodies, Antiphospholipid; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D004041:Dietary Fats; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D004247:DNA