Abstract
ObjectiveEndothelial dysfunction plays a pivotal role in the development of diabetic cardiovascular complications. Accumulation of endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity have been involved in diabetic endothelial dysfunction. This study was to investigate the effect of pyrrolidine dithiocarbamate (PDTC) on impairment of endothelium-dependent vasodilatation in diabetic rats and its potential mechanism.MethodsDiabetic rats were induced by a single intraperitoneal injection of streptozotocin (60mg/kg), and PDTC (10mg/kg) was given in drinking water for 8 weeks. Blood glucose and serum ADMA concentrations were measured in experimental rats. Recombinant adenovirus encoding human DDAH2 gene were constructed and ex vivo transferred to isolated rat aortas. The maximal relaxation (Emax) and half maximal effective concentration (EC50) of aortic rings response to accumulative concentrations of acetylcholine and vascular DDAH activity were examined before and after gene transfection.ResultsDiabetic rats displayed significant elevations of blood glucose and serum ADMA levels compared to control group (P<0.01). Vascular DDAH activity and endothelium-dependent relaxation of aortas were inhibited, as expressed by the decreased Emax and increased EC50 in diabetic rats compared to control rats (P<0.01). Treatment with PDTC not only decreased blood glucose and serum ADMA concentration (P<0.01) but also restored vascular DDAH activity and endothelium-dependent relaxation, evidenced by the higher Emax and lower EC50 in PDTC-treated diabetic rats compared to untreated diabetic rats (P<0.01). Similar restoration of Emax, EC50 and DDAH activity were observed in diabetic aortas after DDAH2-gene transfection.ConclusionsThese results indicate that PDTC could ameliorate impairment of endothelium-dependent relaxation in diabetic rats. The underlying mechanisms might be related to preservation of vascular DDAH activity and consequent reduction of endogenous ADMA in endothelium via its antioxidant action. This study highlights the therapeutic potential of PDTC in impaired vasodilation and provides a new strategy for treatment of diabetic cardiovascular complications.
Highlights
Diabetes mellitus is the most prevalent and serious metabolic disease
These results indicate that pyrrolidine dithiocarbamate (PDTC) could ameliorate impairment of endothelium-dependent relaxation in diabetic rats
The underlying mechanisms might be related to preservation of vascular dimethylarginine dimethylaminohydrolase (DDAH) activity and consequent reduction of endogenous Asymmetric dimethylarginine (ADMA) in endothelium via its antioxidant action
Summary
Diabetes mellitus is the most prevalent and serious metabolic disease. The leading causes of morbidity and mortality among diabetic population are cardiovascular complications. Endothelial dysfunction has been recognized as the early symbol of diabetic cardiovascular complications, and it is characterized by the impairment of endothelium-dependent relaxation mediated by nitric oxide (NO) [1,2,3]. Asymmetric dimethylarginine (ADMA), a homologue of L-arginine, has been identified as the endogenous NOS inhibitor and an independent risk factor for endothelial dysfunction [5]. The major metabolic pathway of ADMA is to be hydrolyzed by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). There are two isoforms of DDAH, DDAH1 and DDAH2 The former is typically located in neuronal tissues of expressing neuronal NOS (nNOS), and the latter predominates in cardiovascular tissues of expressing endothelial NOS (eNOS) [6]. DDAH2 is the key regulator of endogenous ADMA level and NO production in vascular endothelium
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