C-peptide induces vascular smooth muscle cell proliferation -: Involvement of Src-kinase, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinase 1/2
C-peptide induces vascular smooth muscle cell proliferation -: Involvement of Src-kinase, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinase 1/2
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DOI：
10.1161/01.res.0000251231.16993.88
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发表时间：
2006-11-24
影响因子：
20.1
通讯作者：
Marx, Nikolaus
中科院分区：
文献类型：
--
作者：
Walcher, Daniel;Babiak, Christina;Marx, Nikolaus
胰岛素抵抗和早期2型糖尿病患者体内胰岛素原的裂解产物C-肽水平升高。最近的数据表明，C-肽可能通过促进单核细胞和T淋巴细胞重新聚集到血管壁而在动脉粥样硬化形成中发挥潜在的因果作用。本研究检测了C-肽对血管平滑肌细胞(VSMCs)增殖的影响，并评价了相关的细胞内信号转导途径。在糖尿病患者的早期动脉硬化病变中，C-肽与中膜中的VSMCs共存。体外，用C肽刺激人或大鼠VSMCs，以浓度依赖的方式诱导细胞增殖，用[H3]-胸腺肽掺入法显示，人C肽浓度为10nmol/L时，细胞增殖为未刺激细胞的2.6+/-0.8倍(P<；0.05，与未刺激细胞相比，P<；0.05)，0.5nmol/L浓度下，C-肽可诱导VSMCs增殖(与未刺激细胞相比，P<；0.05，n=7)。C肽对VSMC的促增殖作用可被Src短干扰RNA、PP2、PP2、PY294002、ERK1/2抑制剂PD98059所抑制。此外，C-肽还诱导了Src的磷酸化，以及PI-3和ERK1/2的激活，提示这些信号分子参与了C-肽诱导的VSMC增殖。最后，C肽可诱导VSMC中细胞周期蛋白D1的表达和Rb的磷酸化。我们的结果表明，C-肽通过激活Src-和PI-3激酶以及ERK1/2来诱导VSMC的增殖。这些数据表明，C-肽可能参与胰岛素抵抗和早期2型糖尿病患者的斑块形成和再狭窄形成的新机制。
Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes mellitus. Recent data suggest a potential causal role of C-peptide in atherogenesis by promoting monocyte and T-lymphocyte recruitment into the vessel wall. The present study examined the effect of C-peptide on vascular smooth muscle cells (VSMCs) proliferation and evaluated intracellular signaling pathways involved. In early arteriosclerotic lesions of diabetic subjects, C-peptide colocalized with VSMCs in the media. In vitro, stimulation of human or rat VSMCs with C-peptide induced cell proliferation in a concentration-dependent manner with a maximal 2.6 +/- 0.8-fold induction at 10 nmol/L human C-peptide (P < 0.05 compared with unstimulated cells; n=9) and a 1.8 +/- 0.2-fold induction at 0.5nmol/L rat C-peptide (P < 0.05 compared with unstimulated cells; n=7), respectively, as shown by [H3]-thymidin incorporation. The proliferative effect of C-peptide on VSMCs was inhibited by Src short interference RNA transfection, PP2, an inhibitor of Src-kinase, LY294002, an inhibitor of PI-3 kinase, and the ERK1/2 inhibitor PD98059. Moreover, C-peptide induced phosphorylation of Src, as well as activation of PI-3 kinase and ERK1/2, suggesting that these signaling molecules are involved in C-peptide-induced VSMC proliferation. Finally, C-peptide induced cyclin D1 expression as well as phosphorylation of Rb in VSMCs. Our results demonstrate that C-peptide induces VSMC proliferation through activation of Src- and PI-3 kinase as well as ERK1/2. These data suggest a novel mechanism how C-peptide may contribute to plaque development and restenosis formation in patients with insulin resistance and early type 2 diabetes mellitus.