Abstract 474: Biglycan Deficiency is Not Protective Against the Development of Atherosclerosis

Atherosclerosis is the leading cause of death worldwide. As outlined in the Response to Retention hypothesis proteoglycan mediated lipid retention in the vascular wall is thought to be a major cause of atherosclerosis. We and others demonstrated co-localization of the vascular wall matrix proteoglycan biglycan with apoB containing lipoproteins within lesions. Furthermore, we have previously shown that increased biglycan leads to increased atherosclerosis. Thus we hypothesized that biglycan deficiency would attenuate the development of atherosclerosis. Biglycan deficient mice on a mixed genetic background were crossed with LDL receptor deficient mice (C57Bl6). Biglycan deficient and wildtype LDLr-/- mice were fed a 0.12% cholesterol diet for 26 weeks. There were no differences in blood glucose, blood pressure, or triglycerides between genotypes. Total cholesterol progressively increased in both groups over the course of the study and was significantly higher in biglycan deficient compared to wildtype mice at 26 weeks (p<0.05). Biglycan has been proposed to play a role in regulation of TGF-β levels and activity. We previously demonstrated that aged biglycan deficient mice had increased TGF-β levels compared to wildtype. TGF-β was significantly increased in biglycan deficient mice prior to study while fed chow and steadily increased with the high cholesterol diet over the course of the study in both genotypes (p<0.001); however, biglycan deficient mice had significantly more TGF-β at each timepoint compared to wildtype controls (p<0.001). Surprisingly, analysis of the aortic intimal surface revealed a 1.4 fold increase in atherosclerosis in biglycan deficient mice compared to wildtype controls (p=0.07). Thus in opposition to our hypothesis, biglycan deficiency is not protective against the development of atherosclerosis and may exacerbate disease development. Elevated TGF-β and/or cholesterol in biglycan deficient mice may contribute to the increased atherosclerosis observed but further research is required to elicit the mechanism.