Activation of vascular bone morphogenetic protein signaling in diabetes mellitus.
Activation of vascular bone morphogenetic protein signaling in diabetes mellitus.
复制标题
DOI：
10.1161/circresaha.110.236596
复制
发表时间：
2011-02-18
影响因子：
20.1
通讯作者：
Yao Y
中科院分区：
文献类型：
--
作者：
Boström KI;Jumabay M;Matveyenko A;Nicholas SB;Yao Y
糖尿病常并发心血管疾病，如血管钙化和内皮功能障碍，这些都与骨形态发生蛋白（BMP）有关。确定体外高血糖和体内糖尿病是否促进血管BMP活性并与血管钙化相关。增加葡萄糖增加BMP-2和BMP-4的表达; BMP抑制剂基质Gla蛋白（MGP）和头蛋白;激活素样激酶受体（ALK）1、2、3和6; BMP 2型受体;以及人主动脉内皮细胞（HAEC）中的血管内皮生长因子。糖尿病在3种糖尿病动物模型Ins 2 Akita/+小鼠、db/db小鼠和HIP大鼠（人胰岛淀粉样多肽转基因大鼠）（代表1型和2型糖尿病）的主动脉壁中诱导相同因子的表达。条件培养基从葡萄糖处理的HAECs增加血管生成的牛主动脉内皮细胞，如BMP-4介导的，和骨生成的钙化血管细胞，如BMP-2介导的。BMP-4、MGP、ALK 1和ALK 2主要在主动脉内皮侧表达，小干扰RNA实验表明这些基因作为一个组受到调控。糖尿病小鼠和大鼠显示主动脉BMP活性显著增加，如SMAD 1/5/8磷酸化所示。这与骨生成和钙积累增加有关。这些变化在Ins 2Akita/+小鼠中通过使它们与MGP转基因小鼠繁殖来防止，MGP转基因小鼠增加了主动脉BMP抑制。高血压和糖尿病激活血管BMP活性，这有助于促进血管钙化，并且可能受到增加BMP抑制的限制。
Diabetes mellitus is frequently complicated by cardiovascular disease, such as vascular calcification and endothelial dysfunction, which have been associated with bone morphogenetic proteins (BMPs). To determine whether hyperglycemia in vitro and diabetes in vivo promote vascular BMP activity and correlate with vascular calcification. 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. Hyperglycemia and diabetes activate vascular BMP activity, which is instrumental in promoting vascular calcification and may be limited by increasing BMP inhibition.