Increased phosphodiesterase 3A/4B expression after angioplasty and the effect on VASP phosphorylation.
Increased phosphodiesterase 3A/4B expression after angioplasty and the effect on VASP phosphorylation.
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DOI：
10.1016/j.ejphar.2008.05.016
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发表时间：
2008-08
影响因子：
5
通讯作者：
Hong Zhao;Qizhi Guan;Carolyn J. Smith;J. Quilley
中科院分区：
文献类型：
--
作者：
Hong Zhao;Qizhi Guan;Carolyn J. Smith;J. Quilley
冠状动脉血管成形术的有益效果受到血管平滑肌细胞增殖和迁移的限制，导致再狭窄。我们假设血管成形术后磷酸二酯酶（PDE）的活性增加，以响应生长因子，如血小板衍生生长因子（PDGF）-BB和成纤维细胞生长因子（FGF），导致cAMP水平降低，这反过来可能有助于血管平滑肌细胞增殖。在接受血管成形术的大鼠中，主动脉PDE 3/PDE 4的表达和活性在24小时内增加，并与血管扩张剂刺激的磷蛋白（VASP）磷酸化减少有关，VASP是cAMP依赖性蛋白激酶A（PKA）的底物。抑制PDE 3增加血管成形术大鼠主动脉环中VASP磷酸化，而抑制PDE 4或用异丙肾上腺素刺激腺苷酸环化酶没有效果;然而，联合抑制PDE 3和PDE 4对VASP磷酸化产生协同作用。在培养的血管平滑肌细胞中，暴露于PDGF-BB导致PDE 3表达增加，这被PI 3激酶抑制剂阻止，但不能被MAP激酶信号通路抑制剂阻止。相反，FGF增加血管平滑肌细胞中PDE 4的表达，但不影响PDE 3的表达。该研究表明，血管成形术导致PDE的表达/活性增加，这可能是由PDGF-BB和FGF的刺激引起的，并且导致cAMP水平降低，这可能促进再狭窄。这些结果为PDE抑制剂的有益作用提供了合理的解释。
The beneficial effects of coronary angioplasty are limited by the proliferation and migration of vascular smooth muscle cells leading to restenosis. We hypothesized that increased activity of phosphodiesterase (PDE) after angioplasty in response to growth factors such as platelet-derived growth factor (PDGF)-BB and fibroblast growth factor (FGF), leads to reduced cAMP levels, which, in turn, may contribute to vascular smooth muscle cell proliferation. In rats subjected to angioplasty, aortic expression and activity of PDE3/PDE4 were increased within 24 h and associated with reduced phosphorylation of vasodilator-stimulated phosphoprotein (VASP), a substrate for cAMP-dependent protein kinase A (PKA). Inhibition of PDE3 increased VASP phosphorylation in aortic rings from rats subjected to angioplasty, whereas inhibition of PDE4 or stimulation of adenylate cyclase with isoproterenol was without effect; however, combined inhibition of PDE3 and PDE4 produced a synergistic effect on VASP phosphorylation. In cultured vascular smooth muscle cells, exposure to PDGF-BB resulted in increased expression of PDE3, which was prevented by an inhibitor of PI3 kinase but not by inhibitors of the MAP kinase signaling pathway. In contrast, FGF increased the expression of PDE4 in vascular smooth muscle cells but did not influence expression of PDE3. This study shows that angioplasty results in increased expression/activity of PDE, possibly arising from stimulation by PDGF-BB and FGF, and decreased cAMP levels, which may promote restenosis. These results provide a rational explanation for the beneficial effects of PDE inhibitors.