Biosynthesis of H2S is impaired in non-obese diabetic (NOD) mice
Biosynthesis of H2S is impaired in non-obese diabetic (NOD) mice
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DOI：
10.1038/bjp.2008.296
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发表时间：
2008-11-01
影响因子：
7.3
通讯作者：
Cirino, G.
中科院分区：
文献类型：
--
作者：
Brancaleone, V.;Roviezzo, F.;Cirino, G.
背景和目的：硫化氢（H2S）参与了心血管稳态，但其在糖尿病病理学动物模型中的作用的数据仍然缺乏。在这里，我们分析了H2S信号在糖尿病的遗传模型，非肥胖糖尿病（NOD）mice.Experimental approach：NOD小鼠表现出渐进的内皮功能障碍，其特征在于减少反应性的血管糖尿病的发展。根据糖尿值的不同将NOD小鼠分为三组：NOD I、NOD II和NOD III。使用匹配的非肥胖抵抗（NOR）小鼠作为对照。测量血浆和主动脉组织中的H2S水平。在主动脉中的功能研究进行了隔离器官浴使用H2S（NaHS）和代谢前体（L-半胱氨酸）的外源性来源。真实的时间PCR和western blot分析也进行了主动脉组织。关键结果：NOD小鼠表现出进行性降低的H2S血浆水平，这预示着疾病的严重程度。L-半胱氨酸诱导的H2S生产的主动脉组织也逐渐减少。L-半胱氨酸诱导的血管舒张在NOD小鼠中显著减少，而NaHS诱导的舒张不受影响。鸟苷酸环化酶抑制剂（ODQ），L-NAME（NO合成酶抑制剂）或PAG，胱硫醚-γ-裂解酶（CSE）抑制剂抑制H2S的生产诱导L-cystein.Conclusions和影响：在NOD小鼠，内源性H2S的生产显着受损。此外，离体主动脉对外源性H2S的反应能力增强，内皮源性NO似乎参与了L-半胱氨酸向H2S的酶促转化。
Background and purpose: Hydrogen sulphide (H2S) has been involved in cardiovascular homoeostasis but data about its role in animal models of diabetic pathology are still lacking. Here, we have analysed H2S signalling in a genetic model of diabetes, the non-obese diabetic (NOD) mice.Experimental approach: NOD mice exhibit a progressive endothelial dysfunction characterized by a reduced reactivity of blood vessels as diabetes develops. NOD mice were divided into three groups according to different glycosuria values: NOD I, NOD II and NOD III. Age-matched non-obese resistant (NOR) mice were used as controls. H2S levels in plasma and aortic tissue were measured. Functional studies in aorta were carried out in isolated organ baths using both an exogenous source of H2S (NaHS) and the metabolic precursor (L-cysteine). Real time PCR and western blot analysis were also carried out on aortic tissues.Key results: NOD mice exhibited a progressive reduction of H2S plasma levels, which paralleled disease severity. L-cysteine-induced H2S production by aortic tissues was also progressively reduced. L-cysteine-induced vasorelaxation was significantly reduced in NOD mice while NaHS-induced relaxation was unaffected. ODQ (guanylate cyclase inhibitor), L-NAME (NO synthase inhibitor) or PAG, an inhibitor of cystathionine-gamma-lyase (CSE) inhibited H2S production induced by L-cysteine.Conclusions and implications: In NOD mice, endogenous H2S production is significantly impaired. Also, the ability of isolated aorta to respond to exogenous H2S is enhanced and endothelium-derived NO appears to be involved in the enzymatic conversion of L-cysteine into H2S.