TY - JOUR
T1 - Activation of vascular bone morphogenetic protein signaling in diabetes mellitus
AU - Boström, Kristina I.
AU - Jumabay, Medet
AU - Matveyenko, Aleksey
AU - Nicholas, Susanne B.
AU - Yao, Yucheng
N1 - Funding Information:
This work was supported by a grant to U. 8. (FDP USHHS 1 ROl EYO6152-OlAl) by the National Institutes of Health, by a McKnight Scholars Award to U. B., and by the University of California Cancer Research Coordinating Committee funds.
PY - 2011/2/18
Y1 - 2011/2/18
N2 - RATIONALE: Diabetes mellitus is frequently complicated by cardiovascular disease, such as vascular calcification and endothelial dysfunction, which have been associated with bone morphogenetic proteins (BMPs). OBJECTIVE: To determine whether hyperglycemia in vitro and diabetes in vivo promote vascular BMP activity and correlate with vascular calcification. METHODS AND RESULTS: Increased glucose augmented expression of BMP-2 and BMP-4; the BMP inhibitors matrix Gla protein (MGP) and Noggin; activin-like kinase receptor (ALK)1, -2, -3 and -6; the BMP type 2 receptor; and the vascular endothelial growth factor in human aortic endothelial cells (HAECs). Diabetes induced expression of the same factors in the aortic wall of 3 animal models of diabetes, Ins2 mice, db/db mice, and HIP rats (rats transgenic for human islet amyloid polypeptide), representative of types 1 and 2 diabetes. Conditioned media from glucose-treated HAECs increased angiogenesis in bovine aortic endothelial cells, as mediated by BMP-4, and osteogenesis in calcifying vascular cells, as mediated by BMP-2. BMP-4, MGP, ALK1, and ALK2 were predominantly expressed on the endothelial side of the aorta, and small interfering RNA experiments showed that these genes were regulated as a group. Diabetic mice and rats showed a dramatic increase in aortic BMP activity, as demonstrated by SMAD1/5/8 phosphorylation. This was associated with increased osteogenesis and calcium accumulation. These changes were prevented in the Ins2 mice by breeding them with MGP transgenic mice, which increased aortic BMP inhibition. CONCLUSIONS: Hyperglycemia and diabetes activate vascular BMP activity, which is instrumental in promoting vascular calcification and may be limited by increasing BMP inhibition.
AB - RATIONALE: Diabetes mellitus is frequently complicated by cardiovascular disease, such as vascular calcification and endothelial dysfunction, which have been associated with bone morphogenetic proteins (BMPs). OBJECTIVE: To determine whether hyperglycemia in vitro and diabetes in vivo promote vascular BMP activity and correlate with vascular calcification. METHODS AND RESULTS: Increased glucose augmented expression of BMP-2 and BMP-4; the BMP inhibitors matrix Gla protein (MGP) and Noggin; activin-like kinase receptor (ALK)1, -2, -3 and -6; the BMP type 2 receptor; and the vascular endothelial growth factor in human aortic endothelial cells (HAECs). Diabetes induced expression of the same factors in the aortic wall of 3 animal models of diabetes, Ins2 mice, db/db mice, and HIP rats (rats transgenic for human islet amyloid polypeptide), representative of types 1 and 2 diabetes. Conditioned media from glucose-treated HAECs increased angiogenesis in bovine aortic endothelial cells, as mediated by BMP-4, and osteogenesis in calcifying vascular cells, as mediated by BMP-2. BMP-4, MGP, ALK1, and ALK2 were predominantly expressed on the endothelial side of the aorta, and small interfering RNA experiments showed that these genes were regulated as a group. Diabetic mice and rats showed a dramatic increase in aortic BMP activity, as demonstrated by SMAD1/5/8 phosphorylation. This was associated with increased osteogenesis and calcium accumulation. These changes were prevented in the Ins2 mice by breeding them with MGP transgenic mice, which increased aortic BMP inhibition. CONCLUSIONS: Hyperglycemia and diabetes activate vascular BMP activity, which is instrumental in promoting vascular calcification and may be limited by increasing BMP inhibition.
KW - bone morphogenetic protein
KW - diabetes mellitus
KW - endothelial cells
KW - mouse models
KW - vascular calcification
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U2 - 10.1161/CIRCRESAHA.110.236596
DO - 10.1161/CIRCRESAHA.110.236596
M3 - Article
C2 - 21193740
AN - SCOPUS:79952071106
SN - 0009-7330
VL - 108
SP - 446
EP - 457
JO - Circulation research
JF - Circulation research
IS - 4
ER -