Brancaleone V, Roviezzo F, Vellecco V, De Gruttola L, Bucci M, Cirino G
Department of Experimental Pharmacology, University of Naples, Naples, Italy.
Br J Pharmacol. 2008 Nov;155(5):673-80. doi: 10.1038/bjp.2008.296. Epub 2008 Jul 21.
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.
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. H(2)S 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.
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.
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.
硫化氢（H₂S）参与心血管稳态调节，但关于其在糖尿病病理动物模型中作用的数据仍很缺乏。在此，我们分析了糖尿病遗传模型——非肥胖糖尿病（NOD）小鼠中的H₂S信号传导。
随着糖尿病的发展，NOD小鼠表现出以血管反应性降低为特征的进行性内皮功能障碍。根据不同的糖尿值，将NOD小鼠分为三组：NOD I、NOD II和NOD III。将年龄匹配的非肥胖抗性（NOR）小鼠用作对照。测量血浆和主动脉组织中的H₂S水平。在离体器官浴中使用外源性H₂S（硫氢化钠）和代谢前体（L-半胱氨酸）对主动脉进行功能研究。还对主动脉组织进行了实时PCR和蛋白质印迹分析。
NOD小鼠的血浆H₂S水平逐渐降低，这与疾病严重程度平行。主动脉组织中L-半胱氨酸诱导的H₂S生成也逐渐减少。NOD小鼠中L-半胱氨酸诱导的血管舒张明显降低，而硫氢化钠诱导的舒张不受影响。ODQ（鸟苷酸环化酶抑制剂）、L-NAME（一氧化氮合酶抑制剂）或胱硫醚-γ-裂解酶（CSE）抑制剂PAG抑制L-半胱氨酸诱导的H₂S生成。
在NOD小鼠中，内源性H₂S生成明显受损。此外，离体主动脉对外源性H₂S的反应能力增强，内皮衍生的一氧化氮似乎参与了L-半胱氨酸向H₂S的酶促转化。
