Role of Dimethylarginine Dimethylaminohydrolases (DDAH) in pulmonary arterial hypertension
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Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and life- limiting disorder which is associated with impaired bioactivity and/or synthesis of endogenous nitric oxide (NO). The mechanisms resulting in this impairment are multifactorial. Recently, the impact of endogenous NO-synthase inhibitors such as dimethylarginines (ADMA and SDMA) has come into the focus of attention for various endothelial dysfunction associated cardiovascular disorders. As current evidence strongly suggests a central role for endothelial dysfunction in the initiation and progression of pulmonary arterial hypertension (PAH), the plausible role of dimethylarginines is speculated in this disease. Hence forth, the present study was undertaken to investigate the potential role of dimethylarginines in the course of chronic pulmonary hypertension. If this speculation was to be proven, further studies aimed to delineate the precise mechanisms responsible for these alteration including biosynthesis and metabolism of these mediators. These studies were performed mainly on plasma and lung tissues obtained from both IPAH patients and monocrotaline induced pulmonary hypertensive (MCT-PAH) rats. Interestingly, in both MCT-PAH rats and patients suffering from IPAH (NYHA class III and IV), a marked increase in plasma ADMA and SDMA levels compared to their healthy counterparts was observed. These findings were nicely corroborated by increased biosynthesis as evidenced by high expression of asymmetric and symmetric dimethylated arginine proteins in lung tissues from patients suffering from PAH as well as from MCT-PAH rats. Moreover, the main endothelial ADMA metabolizing enzyme, DDAH2, was found to be drastically reduced in IPAH patients and MCT-PAH rat tissue, at both the mRNA and the protein level with no significant changes in DDAH1 expression. The consistency of results seen in human disease and in an established experimental animal model of pulmonary hypertension strongly suggests that changes in dimethylarginine regulation may contribute considerably to the course of the disease. The current study also suggests that novel therapeutics that target the signaling pathway of endogenous NOS inhibitors and promote the functional capacity of DDAH2 would be beneficial for the treatment of IPAH. Interestingly, we identified the phosphodiesterase 3/4 inhibitor, tolafentrine as the first transcriptional modulator of DDAH2 in chronic MCT-PAH rats. Daily repetitive inhalation of tolafentrine by augmenting intracellular cAMP levels restored DDAH expression, activity and nitrite levels that were decreased during the development of MCT-induced PAH. DDAH2 activity restoration was functionally evidenced by near normalized ADMA plasma levels in tolafentrine treated MCT-PAH rats. Furthermore, we also observed a decreased SDMA levels in tolafentrine treated animals, although the mechanisms responsible for this change is not yet clear. Finally, as a regulator of endogenous NOS inhibitors, tolafentrine treatment drastically improved MCT-induced hemodynamic abnormalities and reversed structural and molecular changes underlying MCT induced PAH in rats in the current study.Verknüpfung zu Publikationen oder weiteren Datensätzen
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Giessen : VVB Laufersweiler 2006