Insulin-like growth factor-I regulates proliferation and osteoblastic differentiation of calcifying vascular cells via extracellular signal-regulated protein kinase and phosphatidylinositol 3-kinase pathways
Insulin-like growth factor-I regulates proliferation and osteoblastic differentiation of calcifying vascular cells via extracellular signal-regulated protein kinase and phosphatidylinositol 3-kinase pathways
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DOI：
10.1161/01.res.0000157671.47477.71
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发表时间：
2005-03-04
影响因子：
20.1
通讯作者：
Tintut, Y
中科院分区：
文献类型：
--
作者：
Radcliff, K;Tang, TB;Tintut, Y
血管钙化发生在动脉粥样硬化病变内，其过程类似于成骨。骨源性成骨细胞的旁分泌调节因子之一胰岛素样生长因子- i （IGF-I）也存在于动脉粥样硬化病变中。为了评估其在血管钙化中的可能作用，我们评估了其对钙化血管细胞（CVCs）的体外增殖和分化的影响，CVCs是牛主动脉内侧细胞的一个亚群。结果表明，IGF-I抑制CVC的自发分化和矿化，分别表现为降低碱性磷酸酶（AP）活性和降低基质钙掺入。此外，IGF-I抑制细菌脂多糖、tnf - α或H2O2诱导的AP活性。它还能诱导基于h -3-胸腺嘧啶结合的CVC增殖。Northern分析和使用IGF-I类似物的测试结果表明，IGF-I的作用是通过IGF-I受体介导的。igf - 1还激活细胞外信号调节蛋白激酶（ERK）和磷脂酰肌醇3-激酶（PI3K）途径。抑制ERK或PI3K通路均可逆转IGF-I对CVC增殖和AP活性的影响，提示其有一个共同的下游靶点。ERK激活因子的过表达也模拟了IGF-I对脂多糖诱导的AP活性的抑制。这些结果表明，IGF-I通过ERK和PI3K途径促进血管细胞增殖，抑制成骨细胞分化和矿化。
Vascular calcification develops within atherosclerotic lesions and results from a process similar to osteogenesis. One of the paracrine regulators of bone-derived osteoblasts, insulin-like growth factor-I (IGF-I), is also present in atherosclerotic lesions. To evaluate its possible role in vascular calcification, we assessed its in vitro effects on proliferation and differentiation in calcifying vascular cells (CVCs), a subpopulation of bovine aortic medial cells. Results showed that IGF-I inhibited spontaneous CVC differentiation and mineralization as evidenced by decreased alkaline phosphatase (AP) activity and decreased matrix calcium incorporation, respectively. Furthermore, IGF-I inhibited the AP activity induced by bacterial lipopolysaccharide, TNF-alpha, or H2O2. It also induced CVC proliferation based on H-3-thymidine incorporation. Results from Northern analysis and tests using IGF-I analogs suggest that IGF-I effects are mediated through the IGF-I receptor. IGF-I also activated both the extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) pathways. Inhibition of either the ERK or PI3K pathway reversed IGF-I effects on CVC proliferation and AP activity, suggesting a common downstream target. Overexpression of ERK activator also mimicked IGF-I inhibition of lipopolysaccharide-induced AP activity. These results suggest that IGF-I promotes proliferation and inhibits osteoblastic differentiation and mineralization of vascular cells via both ERK and PI3K pathways.