Hydrogen Sulfide Is an Endogenous Inhibitor of Phosphodiesterase Activity
Hydrogen Sulfide Is an Endogenous Inhibitor of Phosphodiesterase Activity
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DOI：
10.1161/atvbaha.110.209783
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发表时间：
2010-10-01
影响因子：
8.7
通讯作者：
Cirino, Giuseppe
中科院分区：
文献类型：
--
作者：
Bucci, Mariarosaria;Papapetropoulos, Andreas;Cirino, Giuseppe
最近的研究表明，硫化氢（H2S）是由L-半胱氨酸在血管壁内产生的，它调节血管内稳态的几个方面。H2S产生的胱抑素γ-裂解酶（CSE）有助于血管张力，然而，H2S的血管舒张作用的分子机制仍在调查中。方法和结果-使用离体主动脉环，我们观察到，除了L-半胱氨酸导致浓度依赖性的松弛，阻止CSE抑制剂DL-炔丙基甘氨酸（PAG）和β-氰基-L-丙氨酸（BCA）。此外，与PAG或BCA孵育导致硝普钠和异丙肾上腺素诱导的舒张反应发生显著变化。暴露于PAG或BCA的主动脉组织含有较低水平的cGMP，暴露于外源性H2S或CSE过表达的细胞升高cGMP浓度。CSE表达的RNA沉默降低了细胞内cGMP水平，证实了内源性H2S对cGMP积累的积极作用。非选择性磷酸二酯酶抑制剂3-异丁基-1-甲基黄嘌呤大大降低了H2S提高cGMP水平的能力。最后，除了H2S的无细胞系统抑制cGMP和cAMP breakdown. Conclusion-这些研究结果提供了直接的证据，H2S作为内源性抑制剂的磷酸二酯酶活性和加强的概念，这种gasotransmitter可以治疗开发。（Arterioscler Thromb Vasc Biol.2010;30：1998-2004.）
Objective-Recent studies have demonstrated that hydrogen sulfide (H2S) is produced within the vessel wall from L-cysteine regulating several aspects of vascular homeostasis. H2S generated from cystathione gamma-lyase (CSE) contributes to vascular tone; however, the molecular mechanisms underlying the vasorelaxing effects of H2S are still under investigation.Methods and Results-Using isolated aortic rings, we observed that addition of L-cysteine led to a concentration-dependent relaxation that was prevented by the CSE inhibitors DL-propargylglyicine (PAG) and beta-cyano-L-alanine (BCA). Moreover, incubation with PAG or BCA resulted in a rightward shift in sodium nitroprusside-and isoproterenol-induced relaxation. Aortic tissues exposed to PAG or BCA contained lower levels of cGMP, exposure of cells to exogenous H2S or overexpression of CSE raised cGMP concentration. RNA silencing of CSE expression reduced intracellular cGMP levels confirming a positive role for endogenous H2S on cGMP accumulation. The ability of H2S to enhance cGMP levels was greatly reduced by the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Finally, addition of H2S to a cell-free system inhibited both cGMP and cAMP breakdown.Conclusion-These findings provide direct evidence that H2S acts as an endogenous inhibitor of phosphodiesterase activity and reinforce the notion that this gasotransmitter could be therapeutically exploited. (Arterioscler Thromb Vasc Biol. 2010;30:1998-2004.)