Diet-induced Diabetes Activates an Osteogenic Gene Regulatory Program in the Aortas of Low Density Lipoprotein Receptor-deficient Mice

作者：Dwight A. Towler, Miri Bidder, Tammy N. Latifi, Trey Coleman, Clay F. Semenkovich · 发表于：Journal of Biological Chemistry · 年份：1998 · DOI：10.1074/jbc.273.46.30427 · 被引用次数：247 · 研究领域：Bone and Dental Protein Studies、Bone Metabolism and Diseases、Connective tissue disorders research

Vascular calcification is common in people with diabetes and its presence predicts premature mortality. To clarify the underlying mechanisms, we used low density lipoprotein receptor-deficient (LDLR -/-) mice to study vascular calcification in the ascending aorta. LDLR -/- mice on a chow diet did not develop obesity, diabetes, atheroma, or vascular calcification. In contrast, LDLR -/- mice on high fat diets containing cholesterol developed obesity, severe hyperlipidemia, hyperinsulinemic diabetes, and aortic atheroma. A high fat diet without cholesterol also induced obesity and diabetes, but caused only moderate hyperlipidemia and did not result in significant aortic atheroma formation. Regardless of cholesterol content, high fat diets induced mineralization of the proximal aorta (assessed by von Kossa staining) and promoted aortic expression of Msx2 and Msx1, genes encoding homeodomain transcription factors that regulate mineralization and osseous differentiation programs in the developing skull. Osteopontin (Opn), an osteoblast matrix protein gene also expressed by activated macrophages, was up-regulated in the aorta by these high fat diets. In situ hybridization showed that peri-aortic adventitial cells in high fat-fed mice express Msx2. Opn was also detected in this adventitial cell population, but in addition was expressed by aortic vascular smooth muscle cells and macrophages of the intimal atheroma. High fat diets associated with hyperinsulinemic diabetes activate an a...