Abstract
BackgroundThe endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is an independent predictor of cardiovascular and overall mortality. Moreover, elevated ADMA plasma concentrations are associated with the extent of hypertension. However, data from small-sized clinical trials and experimental approaches using murine transgenic models have revealed conflicting results regarding the impact of ADMA and its metabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) in the pathogenesis of hypertension.Methodology/Principal FindingsTherefore, we investigated the role of ADMA and DDAH1 in hypertension-induced end organ damage using the uninephrectomized, deoxycorticosterone actetate salt, and angiotensin II-induced hypertension model in human DDAH1 (hDDAH1) overexpressing and wild-type (WT) mice. ADMA plasma concentrations differed significantly between hDDAH1 and WT mice at baseline, but did not significantly change during the induction of hypertension. hDDAH1 overexpression did not protect against hypertension-induced cardiac fibrosis and hypertrophy. In addition, the hypertension-induced impairment of the endothelium-dependent vasorelaxation of aortic segments ex vivo was not significantly attenuated by hDDAH1 overexpression. However, hDDAH1 mice displayed an attenuated hypertensive inflammatory response in renal tissue, resulting in less hypertensive renal injury.Conclusion/SignificanceOur data reveal that hDDAH1 organ-specifically modulates the inflammatory response in this murine model of hypertension. The lack of protection in cardiac and aortic tissues may be due to DDAH1 tissue selectivity and/or the extent of hypertension by the used combined model. However, our study underlines the potency of hDDAH1 overexpression in modulating inflammatory processes as a crucial step in the pathogenesis of hypertension, which needs further experimental and clinical investigation.
Highlights
The prevalence and morbidity of hypertension is increasing constantly
deoxycorticosterone acetate (DOCA) + angiotensin II (Ang II) did not result in a significant increase of asymmetric dimethylarginine (ADMA) plasma concentrations, neither in WT nor in human DDAH1 (hDDAH1) mice
In contrast to the WT mice, SDMA concentrations significantly increased in hypertensive hDDAH1 mice compared to the normotensive hDDAH1 mice
Summary
The prevalence and morbidity of hypertension is increasing constantly. Despite great achievements in blood pressure therapy, the underlying pathophysiology is still not fully understood. Hypertensive end organ damage is progressing irrespective of the decline in blood pressure. The endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) has emerged as an independent predictor of cardiovascular and overall mortality [2,3,4]. Elevated ADMA plasma concentrations are associated with the incidence of hypertension. There is considerable clinical and experimental evidence that NO deficiency develops as a result of chronic kidney disease and is linked to progression of renal. The endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is an independent predictor of cardiovascular and overall mortality. Elevated ADMA plasma concentrations are associated with the extent of hypertension. Data from small-sized clinical trials and experimental approaches using murine transgenic models have revealed conflicting results regarding the impact of ADMA and its metabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) in the pathogenesis of hypertension
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