Abstract
Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor that blocks nitric oxide production, while congestive heart failure is associated with increased plasma and tissue ADMA content. Increased plasma ADMA is a strong and independent predictor of all-cause mortality in the community and the strongest predictor of mortality in patients after myocardial infarction. Recent studies demonstrated that dimethylarginine dimethylaminohydrolase-1 (DDAH1) is the critical enzyme for ADMA degradation and thereby plays an important role in maintaining cardiovascular nitric oxide bioavailability. Interestingly, activation of the farnesoid X receptor (FXR) through the bile acid ursodeoxycholic acid (UDCA) or synthetic FXR agonists, such as GW4064, can increase DDAH1 expression. Thus, modulating DDAH1 activity through FXR receptor agonists such as UDCA could be a therapeutic target for treating reduced nitric oxide bioavailability in congestive heart failure and other cardiovascular diseases.
Highlights
Congestive heart failure (CHF) is a major cardiovascular disease of epidemic proportion that has increased in prevalence in the past few decades
We recently found that both inducible NOS (iNOS) and endothelial NOS (eNOS) monomer were increased in failing hearts from wild-type mice in response to TAC, and this was associated with increased myocardial superoxide production [21]
In a manner similar to substrate deficiency, several in vitro studies have demonstrated that the addition of ADMA or L-NMMA,which act as a competitive inhibitors of l-arginine, caused O2− generation by purified NO synthase (NOS) protein [22, 37], in cultured human endothelial cells [38, 39], isolated arterioles from rat gracilis muscle [40], and in a murine lung epithelial cell line LA-4 [41]
Summary
Congestive heart failure (CHF) is a major cardiovascular disease of epidemic proportion that has increased in prevalence in the past few decades. In a manner similar to substrate deficiency, several in vitro studies have demonstrated that the addition of ADMA or L-NMMA,which act as a competitive inhibitors of l-arginine, caused O2− generation by purified NOS protein [22, 37], in cultured human endothelial cells [38, 39], isolated arterioles from rat gracilis muscle [40], and in a murine lung epithelial cell line LA-4 [41].
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