High glucose increases the expression of Cbfa1 and BMP-2 and enhances the calcification of vascular smooth muscle cells.
BACKGROUND
Vascular calcification is common in diabetes but the pathogenesis is poorly understood.


METHODS
To investigate the pathogenesis, we first examined the histology of inferior epigastric arteries from diabetic and non-diabetic patients undergoing a renal transplant. To examine the role of hyperglycaemia, bovine vascular smooth muscle cells (BVSMCs) were incubated with normal (5 mM) or high glucose (25 mM) for 48 or 72 h.


RESULTS
The results demonstrated that diabetic patients, compared with non-diabetic patients, had significantly greater calcification and increased expression of the bone matrix proteins osteopontin, type I collagen, bone sialoprotein and alkaline phosphatase (ALP). The in vitro studies demonstrated that high glucose increased the expression of the osteoblast transcription factor core binding factor alpha subunit 1 (Cbfa1) and its downstream protein osteocalcin by 1.9-fold and 1.8-fold, respectively, and ALP activity by 1.5-fold. These findings were blunted in the presence of an inhibitor to protein kinase C. High glucose also significantly enhanced calcification in BVSMC in a time-dependent manner (2.20 +/- 0.50 vs 1.35 +/- 0.55 micromol/mg, day 7; 5.04 +/- 1.35 vs 3.12 +/- 0.92 micromol/mg, day 14; P < 0.05). High glucose also induced the secretion of bone morphogenetic protein-2, a known osteoinductive factor, and further increased the secretion normally seen during calcification by 43% at day 7 and 57% at day 14.


CONCLUSIONS
These results demonstrate that vascular calcification in patients with diabetes is a cell-mediated process characterized by a phenotypic change of VSMCs to osteoblast-like cells with increased bone matrix protein expression, and that hyperglycaemia may directly induce these changes.
Chen
Neal X
NX
Indiana University School of Medicine, 1001 West 10th Street, WD, OPW 526, Indianapolis, IN 46202, USA. xuechen@iupui.edu
Duan
Danxia
D
O'Neill
Kalisha D
KD
Moe
Sharon M
SM
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis*; D002114:Calcinosis / Q000209:etiology*; D002417:Cattle; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis*; D003925:Diabetic Angiopathies / Q000209:etiology*; D005947:Glucose / Q000008:administration & dosage* / Q000502:physiology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D014652:Vascular Diseases / Q000209:etiology*
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D016212:Transforming Growth Factor beta; D005947:Glucose