Caspase-1 deficiency decreases atherosclerosis in apolipoprotein E-null mice

Background

Caspase-1 is a cysteine protease that contributes to mammalian immunity through proteolytic activation of the proinflammatory cytokines, interleukin (IL)-1β 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 cholesterol-enriched 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)-γ 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-γ 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-γ expression.