Cyclic GMP-specific phosphodiesterase 5 regulates growth and apoptosis in pulmonary endothelial cells.
Cyclic GMP-specific phosphodiesterase 5 regulates growth and apoptosis in pulmonary endothelial cells.
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环 GMP 特异性磷酸二酯酶 5 调节肺内皮细胞的生长和凋亡。
DOI：
10.1152/ajplung.00433.2004
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Stevens,Troy
中科院分区：
文献类型：
--
作者：
Zhu,Bing;Strada,Samuel;Stevens,Troy
细胞内cGMP浓度（[cGMP] i）的持续增加抑制细胞生长并诱导细胞凋亡。我们现在报告，cGMP特异性磷酸二酯酶，PDE 5，在调节[cGMP] itransitions，抑制细胞生长和控制易感性肺内皮细胞凋亡中起着主导作用。心房利钠肽（ANP）可激活鸟苷酸环化酶A/B，并诱导肺动脉内皮细胞（PAECs）和肺微血管内皮细胞（PMVECs）的[cGMP]快速升高。然而，PAEC中[cGMP] i的增加是短暂的，并且由于胞质PDE 5水解活性而在10分钟内衰减。由于不存在PDE 5，PMVEC中[cGMP] i的增加持续> 3小时。事实上，在任何ANP浓度下，PMVEC中的持续（30分钟）[cGMP]升高大于PAEC，除非PAEC也用PDE 5抑制剂扎普司特处理。采用RT-PCR、Western blot、免疫沉淀和DEAE层析等方法，我们仅在PAEC中解析PDE 5A1/A2的表达和活性。同样，PDE5表达仅限于体内肺泡外内皮。ANP诱导PMVEC的生长抑制和凋亡，但在PAEC中没有看到类似的效果，除非ANP治疗与扎匹司特相结合。ANP可阻断VEGF诱导的PMVEC增殖和迁移。总的来说，这些数据表明，PDE5调节的[cGMP]控制内皮细胞生长和凋亡，代表了两种内皮表型之间的异质性机制。
Sustained increases in intracellular cGMP concentrations ([cGMP]i) inhibit cell growth and induce apoptosis. We now report that a cGMP-specific phosphodiesterase, PDE5, plays a dominant role in regulating [cGMP]itransitions that inhibit cell growth and control susceptibility to apoptosis in pulmonary endothelium. Atrial natriuretic peptide (ANP) activates guanylyl cyclase A/B and induces a rapid [cGMP]irise 2–5 min after its application, in both pulmonary arterial endothelial cells (PAECs) and pulmonary microvascular endothelial cells (PMVECs). However, increased [cGMP]iin PAECs is transient and decays within 10 min due to cytosolic PDE5 hydrolytic activity. Increased [cGMP]iin PMVECs is sustained for >3 h due to the absence of PDE5. Indeed, at any ANP concentration, the sustained (30 min) [cGMP]irise is greater in PMVECs than in PAECs, unless PAECs are also treated with the PDE5 inhibitor zaprinast. Using RT-PCR, Western blot analysis, immunoprecipitation, and DEAE chromatography, we resolved the expression and activity of PDE 5A1/A2 only in PAECs. Similarly, PDE5 expression was restricted to extra-alveolar endothelium in vivo. ANP induced growth inhibition and apoptosis in PMVECs, but similar effects were not seen in PAECs unless ANP treatment was combined with zaprinast. ANP blocked the VEGF-induced proliferation and migration in PMVECs. Collectively, these data suggest that PDE5-regulated [cGMP]icontrols endothelial cell growth and apoptosis, representing a mechanism of heterogeneity between two endothelial phenotypes.