Molecular mechanisms linking diabetes to the accelerated development of atherosclerosis.

Diabetes mellitus is a major independent risk factor for the development of cardiovascular disease, and both type 1 and type 2 diabetes have been shown to accelerate the development of atherosclerosis, the underlying cause of most myocardial infarctions. Despite the profound clinical importance of vascular disease in patients with diabetes mellitus, our understanding of the relative contributions of insulin resistance and hyperglycemia to atherogenesis is not complete. Furthermore, the molecular and cellular pathways that are involved in disease progression are not clear.

Leptin promotes osteoblast differentiation and mineralization of primary cultures of vascular smooth muscle cells by inhibiting glycogen synthase kinase (GSK)-3β.

In this study, we begin to investigate the underlying mechanism of leptin-induced vascular calcification. We found that treatment of cultured bovine aortic smooth muscle cells (BASMCs) with leptin (0.5-4 μg/ml) induced osteoblast differentiation in a dose-dependent manner.

Oxidized low-density lipoprotein promotes osteoblast differentiation in primary cultures of vascular smooth muscle cells by up-regulating Osterix expression in an Msx2-dependent manner.

We have previously shown that oxidized low-density lipoproteins (oxLDLs) act synergistically with β-glycerophosphate to induce the osteogenic differentiation of primary bovine aortic smooth muscle cells (BASMCs). In the present study, we attempt to resolve the mechanism responsible for this effect by examining the expression of several osteoblast-specific transcription factors. Thus, by culturing BASMCs in the absence or presence of β-glycerophosphate and/or oxLDL, we demonstrate that β-glycerophosphate induces both Runx2 and Osterix (Osx) expression.

Effect of leptin on vascular calcification in apolipoprotein E-deficient mice.

Objective: The adipocytokine leptin has been proposed to increase cardiovascular risk in both obese and diabetic individuals. In the current study, therefore, we used apoE-deficient mice to examine the effects of leptin on both lesion size and calcification.

Methods And Results: Mice were treated with once daily intraperitoneal injections of leptin (125 microg/mouse/d) for 2 months.

Inhibition of osteolytic bone metastasis by unfractionated heparin.

In the current study, we examine heparin's anti-metastatic properties by using a well-defined mouse model of osteolytic bone metastasis. C57BL/6 mice were treated with increasing doses of unfractionated heparin (15, 20, or 25 units/mouse) 30 min prior to the left ventricular injection of GFP-transfected B16F10 melanoma cells. Heparin's effect on tumour burden and bone strength was then quantified 14 days later by bone histomorphometry and biomechanical testing, respectively.