Activation of vascular bone morphogenetic protein signaling in diabetes mellitus

KI Boström, M Jumabay, A Matveyenko… - Circulation …, 2011 - Am Heart Assoc
KI Boström, M Jumabay, A Matveyenko, SB Nicholas, Y Yao
Circulation research, 2011Am Heart Assoc
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 …
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, Ins2Akita/+ 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 Ins2Akita/+ 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.
Am Heart Assoc