Biosynthesis of H2S is impaired in non‐obese diabetic (NOD) mice

Abstract

Background and purpose: Hydrogen sulphide (H 2 S) has been involved in cardiovascular homoeostasis but data about its role in animal models of diabetic pathology are still lacking. Here, we have analysed H 2 S 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. 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 H 2 S (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 H 2 S plasma levels, which paralleled disease severity. L‐cysteine‐induced H 2 S 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‐γ‐lyase (CSE) inhibited H 2 S production induced by L‐cysteine. Conclusions and implications: In NOD mice, endogenous H 2 S production is significantly impaired. Also, the ability of isolated aorta to respond to exogenous H 2 S is enhanced and endothelium‐derived NO appears to be involved in the enzymatic conversion of L‐cysteine into H 2 S. British Journal of Pharmacology (2008) 155, 673–680; doi:fn1; published online 21 July 2008