Journal
CANADIAN JOURNAL OF CARDIOLOGY
Volume 28, Issue 2, Pages 222-229Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cjca.2011.10.013
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Funding
- Canadian Institutes of Health Research [MOP-53344]
- Heart and Stroke Foundation of Canada
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Background: Caspase-1 is a cysteine protease that contributes to mammalian immunity through proteolytic activation of the proinflammatory cytokines, interleukin (IL)-1 beta and IL-18. Methods: To determine if caspase-1 deficiency can protect apolipoprotein E-null (Apoe(-/-)) mice from atherosclerosis, gender-matched, paired-littermate Apoe(-/-) mice with (Casp1(+/+) Apoe(-/-)) or without (Casp1(-/-) Apoe(-/-)) a functional caspase-1 (Casp1) gene were fed either a low fat diet for 26 weeks, or a saturated fat and cholesterolenriched diet for 8 weeks. Plasma lipids and lipoproteins were determined and atherosclerosis was quantified in the aortic sinus and aortic arch. Results: On either diet, caspase-1 deficiency did not affect total serum cholesterol concentrations and lipoprotein-cholesterol distributions. However, caspase-1 deficiency significantly decreased atherosclerosis in the ascending aorta by 35%-45% in both sexes of mice fed either diet. We further examined atherosclerotic lesions for 2 indices of immune cell activation: Major Histocompatibility Complex (MHC) class II and interferon (IFN)-gamma expression. There was a 40%-50% reduction in the number of lesion-associated cells expressing MHC class II from both sexes of Casp1(-/-) Apoe(-/-) mice compared with Casp1(+/-) Apoe(-/-) mice and, a significant reduction in lesion-associated IFN-gamma in female Casp1(-/-) Apoe(-/-) compared with their Casp1(+/+) Apoe(-/-) counterparts. Conclusions: We conclude that caspase-1 promotes atherosclerosis by enhancing the inflammatory status of the lesion through a mechanism likely involving activation of lesion-associated immune cells and IFN-gamma expression.
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