Phosphodiesterases Regulate BAY 41-2272-Induced VASP Phosphorylation in Vascular Smooth Muscle Cells.
Phosphodiesterases Regulate BAY 41-2272-Induced VASP Phosphorylation in Vascular Smooth Muscle Cells.
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DOI：
10.3389/fphar.2012.00010
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发表时间：
2012
影响因子：
5.6
通讯作者：
Tulis DA
中科院分区：
文献类型：
--
作者：
Adderley SP;Joshi CN;Martin DN;Tulis DA
BAY 41-2272（BAY）是可溶性鸟苷酸环化酶的刺激剂，增加环核苷酸并抑制血管平滑肌细胞（VSMC）的增殖。在这项研究中，我们阐明了BAY在调节血管舒张刺激磷蛋白（VASP）的作用机制，重点是VSMC磷酸二酯酶（PDE）。BAY单独增加VASPSer 239和VASPSer 157的磷酸化，分别是PKG和PKA信号传导的指标。IBMX是PDE的非选择性抑制剂，对BAY诱导的VASPSer 239磷酸化没有影响，但抑制VASPSer 157磷酸化。PDE 3或PDE 4的选择性抑制剂减弱BAY介导的VASPSer 239和VASPSer 157的增加，而PDE 5抑制剂仅增强BAY介导的VASPSer 157的增加。相比之下，8Br-cGMP增加了VASPSer 239和VASPSer 157的磷酸化，这两个位点不受选择性PDE抑制剂的影响。在存在8 Br-cAMP的情况下，抑制PDE 4或PDE 5可降低VASPSer 239磷酸化，抑制PDE 3可增加VASPSer 239磷酸化，而抑制PDE 3或PDE 4可增加VASPSer 157磷酸化，抑制PDE 5对VASPSer 157磷酸化无影响。这些发现表明BAY通过cAMP和cGMP沿着PDE的调节来磷酸化VSMC中的VASP，并且BAY在VSMC中的作用机制在VASP磷酸化和PDE的参与方面不同于直接环核苷酸类似物。鉴于VASP作为一种重要的细胞骨架蛋白的作用，这些研究结果为BAY作为VSMC生长的调节剂和抗血管增生性疾病的潜在治疗剂提供了证据。
BAY 41-2272 (BAY), a stimulator of soluble guanylyl cyclase, increases cyclic nucleotides and inhibits proliferation of vascular smooth muscle cells (VSMCs). In this study, we elucidated mechanisms of action of BAY in its regulation of vasodilator-stimulated phosphoprotein (VASP) with an emphasis on VSMC phosphodiesterases (PDEs). BAY alone increased phosphorylation of VASPSer239 and VASPSer157, respective indicators of PKG and PKA signaling. IBMX, a non-selective inhibitor of PDEs, had no effect on BAY-induced phosphorylation at VASPSer239 but inhibited phosphorylation at VASPSer157. Selective inhibitors of PDE3 or PDE4 attenuated BAY-mediated increases at VASPSer239 and VASPSer157, whereas PDE5 inhibition potentiated BAY-mediated increases only at VASPSer157. In comparison, 8Br-cGMP increased phosphorylation at VASPSer239 and VASPSer157 which were not affected by selective PDE inhibitors. In the presence of 8Br-cAMP, inhibition of either PDE4 or PDE5 decreased VASPSer239 phosphorylation and inhibition of PDE3 increased phosphorylation at VASPSer239, while inhibition of PDE3 or PDE4 increased and PDE5 inhibition had no effect on VASPSer157 phosphorylation. These findings demonstrate that BAY operates via cAMP and cGMP along with regulation by PDEs to phosphorylate VASP in VSMCs and that the mechanism of action of BAY in VSMCs is different from that of direct cyclic nucleotide analogs with respect to VASP phosphorylation and the involvement of PDEs. Given a role for VASP as a critical cytoskeletal protein, these findings provide evidence for BAY as a regulator of VSMC growth and a potential therapeutic agent against vasculoproliferative disorders.
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