Reduced atherosclerotic plaque burden in mice with targeted deletion of the discoidin domain receptor 1 (DDR1) gene

Abstract

Vascular smooth muscle cell (SMC) migration, proliferation and matrix metalloproteinase (MMP) expression are critical events in atherosclerotic plaque development and rupture. The discoidin domain receptor 1 (DDR1), a novel collagen receptor tyrosine kinase, is expressed by SMCs and controls the expression of collagen and multiple MMPs. We have previously shown that DDR1 deficient (DDR1−/−) mice develop less intimal thickening after wire injury secondary to decreased MMP-2 and −9 activity and impaired SMC adhesion, proliferation and migration on collagens I and VIII. To assess the involvement of the DDR1 gene in atherogenesis, DDR1−/− mice were crossed with LDL receptor deficient mice (LDLR−/−) to generate mice with a single deficiency in LDLR (DDR1+/+;LDLR−/−) or with a combined deficiency in DDR1 and LDLR (DDR1−/−;LDLR−/−). Mice were fed an atherogenic diet (40% Kcal fat, 1.25% cholesterol) for 12, 24 or 48 weeks. Atherosclerotic plaque burden in the descending aorta was quantified by en face staining with Oil Red O and plaque area in the aortic root was measured using digital histomorphometry. Compared with DDR1+/+;LDLR−/− mice, Oil Red O staining in the descending aortae of DDR1−/−;LDLR−/− mice was significantly reduced at 12 weeks (9.13% vs 2.94%, p<0.05), 24 weeks (33.6% vs 13.5%, p<0.05) and 48 weeks (70.4% vs 42.5%, p<0.05), however plaque area in the aortic root was unaffected at these timepoints. There were no differences in body weight or fasting plasma cholesterol and triglycerides between groups at 12 and 24 weeks. This study is the first to demonstrate the effect of DDR1 deficiency on atherogenesis.