Nitric oxide, generated by the nitric oxide synthase (NOS) enzymes, plays pivotal roles in cardiovascular homeostasis and in the pathogenesis of cardiovascular disease. The NOS cofactor, tetrahydrobiopterin (BH4), is an important regulator of NOS function, since BH4 is required to maintain enzymatic coupling of L-arginine oxidation, to produce NO. Loss or oxidation of BH4 to 7,8-dihydrobiopterin (BH2) is associated with NOS uncoupling, resulting in the production of superoxide rather than NO. In addition to key roles in folate metabolism, dihydrofolate reductase (DHFR) can 'recycle' BH2, and thus regenerate BH4. It is therefore likely that net BH4 cellular bioavailability reflects the balance between de novo BH4 synthesis, loss of BH4 by oxidation to BH2, and the regeneration of BH4 by DHFR. Recent studies have implicated BH4 recycling in the direct regulation of eNOS uncoupling, showing that inhibition of BH4 recycling using DHFR-specific siRNA and methotrexate treatment leads to eNOS uncoupling in endothelial cells and the hph-1 mouse model of BH4 deficiency, even in the absence of oxidative stress. These studies indicate that not only BH4 level, but the recycling pathways regulating BH4 bioavailability represent potential therapeutic targets and will be discussed in this review.
"Reduced activity and/or level of BH 4 favor(s) the generation of a superoxide anion (O 2 @BULLET− ) instead of NO, resulting in endothelial dysfunction   . Altogether, this indicates that elevated plasma TCh levels may result in reduced NO synthesis via several mechanisms, leading to endothelial dysfunction. "
[Show abstract][Hide abstract] ABSTRACT: Maternal physiological hypercholesterolemia occurs during pregnancy, ensuring normal fetal development. In some cases, the maternal plasma cholesterol level increases to above this physiological range, leading to maternal supraphysiological hypercholesterolemia (MSPH). This condition results in endothelial dysfunction and atherosclerosis in the fetal and placental vasculature. The fetal and placental endothelial dysfunction is related to alterations in the L-arginine/nitric oxide (NO) pathway and the arginase/urea pathway and results in reduced NO production. The level of tetrahydrobiopterin (BH4), a cofactor for endothelial NO synthase (eNOS), is reduced in nonpregnant women who have hypercholesterolemia, which favors the generation of the superoxide anion rather than NO (from eNOS), causing endothelial dysfunction. However, it is unknown whether MSPH is associated with changes in the level or metabolism of BH4; as a result, eNOS function is not well understood. This review summarizes the available information on the potential link between MSPH and BH4 in causing human fetoplacental vascular endothelial dysfunction, which may be crucial for understanding the deleterious effects of MSPH on fetal growth and development.
Oxidative Medicine and Cellular Longevity 08/2015; · 3.36 Impact Factor
"Using NADPH as a source of reducing equivalents, sepiapterin reductase (SPR) catalyzes the reduction of sepiapterin to dihydrobiopterin (BH2), a precursor for tetrahydrobiopterin (BH4), an important cofactor in nitric oxide biosynthesis and alkylglycerol and aromatic amino acid metabolism (Thony et al., 2000; Crabtree and Channon, 2011; Werner et al., 2011; Watschinger and Werner, 2013) (see Fig. 1 showing reactions of sepiapterin reductase). SPR is widely distributed in tissues, including lung, liver, kidney, and brain (Kato, 1971). "
[Show abstract][Hide abstract] ABSTRACT: Sepiapterin reductase (SPR) catalyzes the reduction of sepiapterin to dihydrobiopterin (BH2), the precursor for tetrahydrobiopterin (BH4), a cofactor critical for nitric oxide biosynthesis and alkylglycerol and aromatic amino acid metabolism. SPR also mediates chemical redox cycling, catalyzing one electron reduction of redox active chemicals including quinones and bipyridinium herbicides (e.g., menadione, 9,10-phenanthrenequinone and diquat); rapid reaction of the reduced radicals with molecular oxygen generates reactive oxygen species (ROS). Using recombinant human SPR, sulfonamide and sulfonylurea based sulfa drugs were found to be potent non-competitive inhibitors of both sepiapterin reduction and redox cycling. The most potent inhibitors of sepiapterin reduction (IC50's = 31-180 nM) were sulfasalazine, sulfathiazole, sulfapyridine, sulfamethoxazole and chlorpropamide. Higher concentrations of the sulfa drugs (IC50's = 0.37-19.4 µM) were required to inhibit redox cycling, presumably due to distinct mechanisms of sepiapterin reduction and redox cycling. In PC12 cells, which generate catecholamine and monoamine neurotransmitters via BH4-dependent amino acid hydroxylases, sulfa drugs inhibited both BH2/BH4 biosynthesis and redox cycling mediated by SPR. Inhibition of BH2/BH4 resulted in decreased production of dopamine and dopamine metabolites, 3, 4-dihydroxyphenylacetic acid and homovanillic acid, and 5-hydroxytryptamine. Sulfathiazole (200 µM) markedly suppressed neurotransmitter production, an effect reversed by BH4. These data suggest that SPR and BH4-dependent enzymes, are 'off-targets' of sulfa drugs, which may underlie their untoward effects. The ability of the sulfa drugs to inhibit redox cycling may ameliorate ROS-mediated toxicity generated by redox active drugs and chemicals, contributing to their anti-inflammatory activity.
The American Society for Pharmacology and Experimental Therapeutics.
Journal of Pharmacology and Experimental Therapeutics 12/2014; 352(3). DOI:10.1124/jpet.114.221572 · 3.97 Impact Factor
"Importantly, BH4 is an essential cofactor for eNOS. When BH4 levels are inadequate, eNOS is no longer coupled with L-arginine oxidation, which results in ROS rather than NO production, thereby inducing vascular endothelial dysfunction . So, the association between Hcy and endothelial dysfunction depends largely on its damaging effect on eNOS coupling. "
[Show abstract][Hide abstract] ABSTRACT: Increased oxidative stress, alterations of lipid metabolism and induction of thrombosis have been suggested to be pathogenic links which are present between hyperhomocysteinaemia and atherosclerosis. However, the mechanism by which homocysteine (Hcy) can promote atherogenesis is far from clear and it has been debated. In the presence of cardiovascular risk factors, endothelial dysfunction is the central commodity which converges a plenty of factors, which have been named as atherogenic. Now-a-days, there are only few studies which have presented the correlation between antioxidant enzyme HDL-associated-paraoxonase 1(PON1) and Hcy in atherosclerosis. Both PON 1 and Hcy have been implicated in human diseases which are related to endothelial dysfunction. Although paraoxonases have the ability to hydrolyze a variety of substrates, only one of them, Hcy-thiolactone, is known to occur naturally. It seems very likely that the involvement of Hcy in atherosclerotic disease is mediated through its interactions with PON1.
Journal of Clinical and Diagnostic Research 09/2014; 8(9). DOI:10.7860/JCDR/2014/7827.4773 · 0.23 Impact Factor
Mariam El Assar, Javier Angulo, Leocadio Rodríguez-Mañas
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