Chronic insulin treatment amplifies PDGF-induced motility in differentiated aortic smooth muscle cells by suppressing the expression and function of PTP1B.
Chronic insulin treatment amplifies PDGF-induced motility in differentiated aortic smooth muscle cells by suppressing the expression and function of PTP1B.
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长期胰岛素治疗通过抑制 PTP1B 的表达和功能，放大 PDGF 诱导的分化主动脉平滑肌细胞的运动。
DOI：
10.1152/ajpheart.01105.2007
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Hassid,Aviv
中科院分区：
文献类型：
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作者：
Zhuang,Daming;Pu,Qinghua;Ceacareanu,Bogdan;Chang,Yingzi;Dixit,Madhulika;Hassid,Aviv
高胰岛素血症在血管疾病的发病机制中起主要作用。在高胰岛素血症中，再狭窄的发生率加快，并依赖于血管平滑肌细胞从中膜向新生内膜运动的增加。PDGF在血管损伤模型中介导新生内膜形成中起关键作用。我们已经报道了PDGF增加蛋白酪氨酸磷酸酶PTP 1B的水平，PTP 1B抑制PDGF诱导的培养细胞的运动性，并减弱损伤的颈动脉中新生内膜的形成。其他人报道胰岛素增强PDGF在培养的平滑肌细胞中的促有丝分裂和运动发生作用，并且高胰岛素血症促进血管重塑。在本研究中，我们测试了胰岛素通过抑制PTP 1B的表达和功能来增强PDGF诱导的细胞运动性的假设。我们发现，慢性而不是急性治疗的细胞与胰岛素增强PDGF诱导的运动在分化培养的原代大鼠主动脉平滑肌细胞，它抑制PDGF诱导的PTP 1B蛋白的上调。此外，胰岛素抑制PDGF诱导的PTP 1B mRNA水平上调、PTP 1B酶活性和PTP 1B与PDGF受体-β的结合，并增强PDGF诱导的PDGF受体磷酸化。胰岛素治疗诱导磷脂酰肌醇3-激酶（PI 3-激酶）-δ的时间依赖性上调和Akt（PI 3-激酶下游的一种酶）的活化。最后，通过药理学或遗传学手段抑制PI 3-激酶活性或其功能可挽救胰岛素处理细胞中的PTP 1B活性。这些观察揭示了解释胰岛素如何放大关键生长因子PDGF的运动能力的新机制。
Hyperinsulinemia plays a major role in the pathogenesis of vascular disease. Restenosis occurs at an accelerated rate in hyperinsulinemia and is dependent on increased vascular smooth muscle cell movement from media to neointima. PDGF plays a critical role in mediating neointima formation in models of vascular injury. We have reported that PDGF increases the levels of protein tyrosine phosphatase PTP1B and that PTP1B suppresses PDGF-induced motility in cultured cells and that it attenuates neointima formation in injured carotid arteries. Others have reported that insulin enhances the mitogenic and motogenic effects of PDGF in cultured smooth muscle cells and that hyperinsulinemia promotes vascular remodeling. In the present study, we tested the hypothesis that insulin amplifies PDGF-induced cell motility by suppressing the expression and function of PTP1B. We found that chronic but not acute treatment of cells with insulin enhances PDGF-induced motility in differentiated cultured primary rat aortic smooth muscle cells and that it suppresses PDGF-induced upregulation of PTP1B protein. Moreover, insulin suppresses PDGF-induced upregulation of PTP1B mRNA levels, PTP1B enzyme activity, and binding of PTP1B to the PDGF receptor-β, and it enhances PDGF-induced PDGF receptor phosphotyrosylation. Treatment with insulin induces time-dependent upregulation of phosphatidylinositol 3-kinase (PI3-kinase)-δ and activation of Akt, an enzyme downstream of PI3-kinase. Finally, inhibition of PI3-kinase activity, or its function, by pharmacological or genetic means rescues PTP1B activity in insulin-treated cells. These observations uncover novel mechanisms that explain how insulin amplifies the motogenic capacity of the pivotal growth factor PDGF.