First Cardiovascular Division, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Tao-Yuan, Taiwan.
Arterioscler Thromb Vasc Biol. 2011 Sep;31(9):2106-13. doi: 10.1161/ATVBAHA.111.230987. Epub 2011 Jun 16.
Cilostazol, a potent type 3 phosphodiesterase inhibitor, has recently been found to reduce neointimal formation by inhibiting vascular smooth muscle cell (VSMC) proliferation. The aim of this study is to investigate whether cilostazol exerts an action on phenotypic modulation of VSMCs, another important process in the pathogenesis of neointimal formation.
Cilostazol may convert VSMCs from a serum-induced dedifferentiation state to a differentiated state, as indicated by a spindle-shaped morphology and an increase in the expression of smooth muscle cell differentiation marker contractile proteins. The upregulation of contractile proteins by cilostazol involves the cAMP/protein kinase A (PKA) signaling pathway, because the cAMP analog mimicked and specific cAMP/PKA inhibitors opposed the effect of cilostazol. Furthermore, cilostazol-activated cAMP response element (CRE)-binding protein (CREB), including phosphorylation at Ser133 and its nuclear translocation. Deletion and mutational analysis of the contractile protein promoters along with chromatin immunoprecipitation using anti-CREB antibody showed that CRE is essential for cilostazol-induced contractile protein expression. Transfection of dominant-negative CREB (mutated Ser133) plasmid in VSMCs blocked cilostazol-stimulated contractile protein expression. In vivo, cilostazol upregulated contractile proteins and induced the activation of CREB in the neointima of balloon-injured arteries.
Cilostazol promotes VSMC differentiation through the cAMP/PKA/CREB signaling cascade.
西洛他唑是一种强效的 3 型磷酸二酯酶抑制剂，最近发现它通过抑制血管平滑肌细胞（VSMC）增殖来减少新生内膜形成。本研究旨在探讨西洛他唑是否对 VSMC 的表型调节有作用，VSMC 的表型调节是新生内膜形成发病机制中的另一个重要过程。
西洛他唑可能使 VSMC 从血清诱导的去分化状态转变为分化状态，表现为梭形形态和收缩蛋白等平滑肌细胞分化标志物的表达增加。西洛他唑对收缩蛋白的上调涉及环磷酸腺苷/蛋白激酶 A（PKA）信号通路，因为环磷酸腺苷类似物模拟了西洛他唑的作用，而特定的环磷酸腺苷/蛋白激酶 A 抑制剂则拮抗了西洛他唑的作用。此外，西洛他唑激活了 cAMP 反应元件（CRE）结合蛋白（CREB），包括 Ser133 位点的磷酸化及其核转位。收缩蛋白启动子的缺失和突变分析以及使用抗 CREB 抗体的染色质免疫沉淀显示，CRE 对于西洛他唑诱导的收缩蛋白表达是必需的。在 VSMC 中转染显性失活 CREB（突变 Ser133）质粒可阻断西洛他唑刺激的收缩蛋白表达。在体内，西洛他唑上调了收缩蛋白，并诱导了球囊损伤动脉新生内膜中 CREB 的激活。
西洛他唑通过 cAMP/PKA/CREB 信号级联促进 VSMC 分化。
