Role of DDAH-1 in lipid peroxidation product-mediated inhibition of endothelial NO generation

Abstract

Altered nitric oxide (NO) biosynthesis is thought to play a role in the initiation and progression of atherosclerosis and may contribute to increased risk seen in other cardiovascular diseases. It is hypothesized that altered NO bioavailability may result from an increase in endogenous NO synthase (NOS) inhibitors, asymmetric dimethly araginine (ADMA), and N(G)-monomethyl arginine, which are normally metabolized by dimethyarginine dimethylamine hydrolase (DDAH). Lipid hydroperoxides and their degradation products are generated during inflammation and oxidative stress and have been implicated in the pathogenesis of cardiovascular disorders. Here, we show that the lipid hydroperoxide degradation product 4-hydroxy-2-nonenal (4-HNE) causes a dose-dependent decrease in NO generation from bovine aortic endothelial cells, accompanied by a decrease in DDAH enzyme activity. The inhibitory effects of 4-HNE (50 microM) on endothelial NO production were partially reversed with L-Arg supplementation (1 mM). Overexpression of human DDAH-1 along with antioxidant supplementation completely restored endothelial NO production following exposure to 4-HNE (50 microM). These results demonstrate a critical role for the endogenous methylarginines in the pathogenesis of endothelial dysfunction. Because lipid hydroperoxides and their degradation products are known to be involved in atherosclerosis, modulation of DDAH and methylarginines may serve as a novel therapeutic target in the treatment of cardiovascular disorders associated with oxidative stress.

Supplementation of a γ-tocopherol-rich mixture of tocopherols in healthy men protects against vascular endothelial dysfunction induced by postprandial hyperglycemia

“…Currently, no evidence indicates that hyperglycemia or oxidative stress regulates PRMT activity. However, studies in vitro demonstrate that incubation of endothelial cells with glucose or end products of lipid peroxidation increases ADMA by suppressing its DDAH-dependent degradation [39,40]. In contrast, our work indicates that postprandial concentrations of ADMA are unaffected following glucose ingestion.…”

Role of Dimethylarginine Dimethylaminohydrolases in the Regulation of Endothelial Nitric Oxide Production

“…Recently, several groups have demonstrated that modulating DDAH activity can have a profound effect on endothelial NO production (8, 9, 11, 20, 21, 23-25, 34, 35). In this regard, our group and others have shown that overexpression of DDAH-1 results in increased NO production (9,36). Furthermore, oxidized low density lipoprotein and tumor necrosis factor ␣ have been shown to decrease DDAH activity, leading to decreased endothelial NO production (37).…”

“…Furthermore, oxidized low density lipoprotein and tumor necrosis factor ␣ have been shown to decrease DDAH activity, leading to decreased endothelial NO production (37). It has also been demonstrated that 4-hyrdoxynonenal, the highly reactive oxidant product of lipid peroxidation, inhibits DDAH activity and leads to impaired NO generation through the formation of Michael addition products in the catalytic triad of DDAH (36). Thus, evidence suggests that DDAH-1 activity is under redox control, and loss of enzyme function impairs endothelial NO generation.…”

Supplementation with Phycocyanobilin, Citrulline, Taurine, and Supranutritional Doses of Folic Acid and Biotin—Potential for Preventing or Slowing the Progression of Diabetic Complications

“…Oxidative stress impairs effective NO activity in several ways: oxidizing tetrahydrobiopterin; inhibiting dimethylarginine dimethylaminohydrolase (DDAH), and thereby boosting intracellular levels of the eNOS inhibitor/uncoupler asymmetric dimethylarginine (ADMA) [115,116,117,118,119]; and direct quenching of NO by superoxide, leading to production of the potent oxidant peroxynitrite. Peroxynitrite is a mediator of the oxidation of tetrahydrobiopterin; and it can also inhibit a key target of NO bioactivity, soluble guanylate cyclase (sGC), by oxidizing the ferrous iron in its attached heme group [120,121,122,123].…”