High glucose increases the expression of Cbfa1 and BMP-2 and enhances the calcification of vascular smooth muscle cells

Xuening (Neal) Chen, Danxia Duan, Kalisha D. O'Neill, Sharon Moe

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

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 μmol/mg, day 7; 5.04 ± 1.35 vs 3.12 ± 0.92 μmol/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.

Original languageEnglish
Pages (from-to)3435-3442
Number of pages8
JournalNephrology Dialysis Transplantation
Volume21
Issue number12
DOIs
StatePublished - Dec 1 2006

Fingerprint

Core Binding Factor Alpha 1 Subunit
Vascular Smooth Muscle
Smooth Muscle Myocytes
Vascular Calcification
Glucose
Bone Matrix
Osteopontin
Osteoblasts
Hyperglycemia
Alkaline Phosphatase
Epigastric Arteries
Bone Morphogenetic Protein 2
Proteins
Osteocalcin
Collagen Type I
Protein Kinase C
Histology
Transcription Factors
Transplants
Kidney

Keywords

  • Bone matrix proteins
  • Bone morphogenic protein-2 (BMP-2)
  • Core binding factor alpha-1 (Cbfa1)
  • High glucose
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

Cite this

High glucose increases the expression of Cbfa1 and BMP-2 and enhances the calcification of vascular smooth muscle cells. / Chen, Xuening (Neal); Duan, Danxia; O'Neill, Kalisha D.; Moe, Sharon.

In: Nephrology Dialysis Transplantation, Vol. 21, No. 12, 01.12.2006, p. 3435-3442.

Research output: Contribution to journalArticle

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AU - Duan, Danxia

AU - O'Neill, Kalisha D.

AU - Moe, Sharon

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N2 - 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 μmol/mg, day 7; 5.04 ± 1.35 vs 3.12 ± 0.92 μmol/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.

AB - 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 μmol/mg, day 7; 5.04 ± 1.35 vs 3.12 ± 0.92 μmol/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.

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