Diabetes mellitus accelerates cartilaginous metaplasia and calcification in atherosclerotic vessels of LDLr mutant mice

Background ar calcification is highly prevalent in patients with type II diabetes mellitus (T2DM). Little is known about whether T2DM is causative. s nsity lipoprotein receptor mutant (LDLr−/−) mice were fed with customized diabetogenic and/or procalcific diets to induce atherosclerosis, cartilaginous metaplasia and calcification, along with obesity, hyperglycemia, hyperinsulinemia, and hypercholesterolemia at various levels, and euthanized for study after 18–24 weeks on diet. s nd that T2DM accelerated cartilaginous and calcific lesion development by ~ 3- and 13-fold as determined by incidence of vascular cartilaginous metaplasia and calcification in LDLr−/− mice. Lowering dietary fat from ~ 60% to ~ 40% kcal reduced body weight and serum glucose and insulin levels, leading to a 2-fold decrease in aortic calcium content. Correlation analysis of calcium content with a calculated insulin resistance index, homeostasis model assessment of insulin resistance, showed a positive correlation of insulin resistance with vascular calcification. Finally, we used genetic fate mapping strategy to trace cells of SM origin in these animals. Vascular smooth muscle cells (SMCs) were found to be a major cell source contributing to osteochondrogenic differentiation and calcification. Receptor for advanced glycation end-products (RAGE) was up-regulated, co-localizing with osteochondrogenic SMCs. sions h quantitative measure of aortic calcium content, we provided experimental findings that LDLr−/− mice, like T2DM patients, are predisposed to vascular calcification. Our study is also the first to establish a distinct role of hyperglycemia and hypercholesterolemia in osteochondrogenic differentiation of SMCs and determined these cells as a major source contributing to cartilaginous and calcifying lesions of T2DM blood vessels, possibly mediated by RAGE.