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Abstract
Cardiovascular diseases, caused by atherosclerosis or hardening of the arteries, are the number one cause of death in the world, causing over 30% of deaths. Diabetes is also becoming an increasingly common disease with nearly 10% of Americans diagnosed with diabetes. Diabetes is known to increase macrophage expression and inflammatory activation leading to increased risk of death by 50%. Macrophages are important inflammatory response cells that are present in every stage of atherosclerosis and may become a target for emerging strategies to combat atherosclerosis. Versican is an extracellular matrix protein that is found in higher levels in diabetic individuals and is associated with increased atherosclerosis. Therefore, it is hypothesized that if the versican gene is knocked out, there will be fewer apoptotic cells, less inflammation, and slower atherosclerotic progression. To determine how versican and diabetes affect lipid loading, inflammation, and apoptosis, a combination of cholesterol assays; versican staining; qPCR for Il1b, Il6, Ccl2, and Il110; TUNEL; and necrosis/macrophage viability was utilized. Overall, diabetes increased necrotic core and cholesterol loading, but did not alter lesion size. Diabetes also increased expression of Il1b, Ccl2, and Il10. While versican reduced necrotic core size under diabetic conditions, it did not alter lipid or cholesterol loading nor inflammatory cytokine expression for Il1b, Il6, Ccl2, or Il10. In addition, there was no significant effect of diabetes or versican on the number of apoptotic cells associated with macrophages or free within the plaque. Finally, diabetes, but not versican-deficiency, increased necrosis in isolated peritoneal macrophages. Altogether, these results suggest that diabetes has a greater effect on lipid loading and inflammation. The presence of versican in diabetic and inflammatory conditions has been observed, but its role in the progression of these diseases is still not fully understood. Additional research is needed to further evaluate the impact of versican on efferocytosis and atherosclerotic progression.
