Heparin Inhibits Activation of Latent Transforming Growth Factor-β1
Heparin Inhibits Activation of Latent Transforming Growth Factor-β1
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DOI：
10.1159/000355837
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发表时间：
2013-01-01
期刊：
影响因子：
3.1
通讯作者：
Lee, Mee Jeong
中科院分区：
文献类型：
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作者：
Lee, Mee Jeong
目的：肝素除了作为抗凝剂外，还具有抗纤维化作用。转化生长因子-β(1) (TGF-β(1)) 以潜在的 TGF-β(1) (LTGF-β(1)) 形式从细胞中分泌。 LTGF-β(1) 由 TGF-β(1) 和潜伏相关肽 (LAP) 组成。为了具有生物活性，TGF-β(1) 必须从 LAP 中释放出来。肝素与 LAP 以及 TGF-β(1) 结合 本研究旨在探讨肝素与 LTGF-β(1) 相互作用的生物学效应。材料和方法：通过 ELISA 测量 TGF-β(1)。使用荧光底物 Pyr-Arg-Thr-LysArg-AMC 测定弗林蛋白酶样前蛋白转化酶活性。结果：肝素不干扰TGF-β(1)受体结合，但抑制弗林蛋白酶样前蛋白转化酶介导的血小板LTGF-β(1)激活。这不是通过抑制酶来实现的，因为肝素不会抑制弗林蛋白酶样前蛋白转化酶的活性。此外，肝素还能抑制培养细胞上清液中分泌的重组小LTGF-β(1)、血小板LTGF-β(1)和LTGF-β(1)的酸活化。低分子量肝素，包括达肝素、依诺肝素和那屈肝素，也对血小板 LTGF-β(1) 的弗林样前蛋白转化酶介导的或酸激活具有抑制作用。结论：研究结果表明，肝素可能通过同时与 TGF-β(1) 和 LAP 结合而使 LTGF-β(1) 抵抗激活。肝素对 LTGF-β(1) 激活的抑制可能部分解释了其抗纤维化作用。 (C) 2013 S. Karger AG，巴塞尔
Aim: Besides acting as an anticoagulant, heparin has antifibrotic effects. Transforming growth factor-beta(1) (TGF-beta(1)) is secreted from cells as latent TGF-beta(1) (LTGF-beta(1)). LTGF-beta(1) consists of TGF-beta(1) and latency-associated peptide (LAP). To be biologically active, TGF-beta(1) has to be released from LAP. Heparin binds to LAP as well as TGF-beta(1) This study was performed to explore the biological effect of the interaction of heparin with LTGF-beta(1). Materials and Methods: TGF-beta(1) was measured by ELISA. Furin-like proprotein convertase activity was assayed using the fluorogenic substrate, Pyr-Arg-Thr-LysArg-AMC. Results: Heparin did not interfere with the receptor binding of TGF-beta(1), but inhibited furin-like proprotein convertase-mediated activation of platelet LTGF-beta(1). This was not by inhibition of the enzyme because heparin did not inhibit the activity of furin-like proprotein convertase. In addition, heparin inhibited acid activations of recombinant small LTGF-beta(1), platelet LTGF-beta(1) and LTGF-beta(1)s secreted in the supernatant of cultured cells. Low-molecular-weight heparins, including dalteparin, enoxaparin and nadroparin, also had inhibitory effects on furin-like proprotein convertasemediated or acid activation of platelet LTGF-beta(1). Conclusion: The findings suggest that heparin renders LTGF-beta(1) resistant to activation, possibly by binding simultaneously to TGF-beta(1) and LAP. Inhibition of LTGF-beta(1) activation by heparin may in part account for its antifibrotic effects. (C) 2013 S. Karger AG, Basel