Antigrowth properties of BAY 41-2272 in vascular smooth muscle cells.
Antigrowth properties of BAY 41-2272 in vascular smooth muscle cells.
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DOI：
10.1097/fjc.0b013e31819715c4
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发表时间：
2009-02
影响因子：
3
通讯作者：
Tulis DA
中科院分区：
文献类型：
--
作者：
Mendelev NN;Williams VS;Tulis DA
血管平滑肌（VSM）的生长在血管疾病的病理生理中是不可或缺的，确定有能力调节VSM生长的方法至关重要。环核苷酸信号通常被认为对心脏和血管组织具有保护作用，并已成为许多基础科学和临床研究的目标。本项目分析了最近发现的可溶性鸟苷酸环化酶（sGC）刺激剂和环鸟苷单磷酸（cGMP）合成诱导性物质BAY 41-2272 （BAY）对VSM细胞生长的影响。在大鼠A7R5 VSM细胞中，BAY以剂量和时间依赖性的方式显著降低增殖。BAY激活cGMP和环腺苷单磷酸（cAMP）信号，cGMP和cAMP含量升高，环核苷酸依赖性蛋白激酶表达增加，差异血管扩张剂刺激磷酸蛋白（VASP）磷酸化。BAY显著提高了细胞周期蛋白E的表达，降低了细胞周期蛋白依赖性激酶(Cdk)-2和-6的表达，增加了细胞周期抑制蛋白p21WAF1/Cip1和p27Kip1的表达，降低了磷酸化局灶黏附激酶（FAK）的表达。这些综合研究结果首次证明了血管内皮素抑制剂BAY 41-2272在血管内皮素中的抗生长和细胞周期调控特性，并为其在临床和基础心血管科学中的进一步研究提供了支持。
Vascular smooth muscle (VSM) growth is integral in the pathophysiology of blood vessel diseases, and identifying approaches that have capacity to regulate VSM growth is critically essential. Cyclic nucleotide signaling has been generally considered protective in cardiac and vascular tissues and has been the target of numerous basic science and clinical studies. In this project, the influence of BAY 41-2272 (BAY), a recently described soluble guanylate cyclase (sGC) stimulator and inducer of cyclic guanosine monophosphate (cGMP) synthesis, on VSM cell growth was analyzed. In rat A7R5 VSM cells BAY significantly reduced proliferation in dose- and time-dependent fashion. BAY activated cGMP and cyclic adenosine monophosphate (cAMP) signaling evidenced through elevated cGMP and cAMP content, increased expression of cyclic nucleotide-dependent protein kinases, and differential vasodilator-stimulated phosphoprotein (VASP) phosphorylation. BAY significantly elevated cyclin E expression, decreased expression of the regulatory cyclin-dependent kinases (Cdk)-2 and -6, increased expression of cell cycle inhibitory p21WAF1/Cip1 and p27Kip1, and reduced expression of phosphorylated focal adhesion kinase (FAK). These comprehensive findings provide first evidence for the anti-growth, cell cycle-regulatory properties of the neoteric agent BAY 41-2272 in VSM and lend support for its continued study in the clinical and basic cardiovascular sciences.