Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease.
ABSTRACT 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.
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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 PON1.09/2014; 8.
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ABSTRACT: Figure optionsDownload full-size imageDownload high-quality image (364 K)Download as PowerPoint slideFree Radical Biology and Medicine. 01/2014;
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ABSTRACT: The aim of the present study was to conduct an updated meta-analysis of relevant randomized controlled trials (RCTs) in order to estimate the effect of folic acid supplementation on endothelial function and the concentration of plasma homocysteine in patients with coronary artery disease (CAD). An extensive search of PubMed was conducted to identify RCTs that compared folic acid with placebo therapy. The mean difference (MD) and 95% confidence interval (CI) were used as a measure of the correlation between folic acid supplementation and endothelial function/plasma homocysteine concentration. Of the 377 patients included in this analysis, 191 patients underwent folic acid supplementation and 186 individuals underwent placebo treatment. Compared with the use of a placebo, folic acid supplementation alone exhibited significant efficacy on increasing flow-mediated dilation (FMD; MD, 57.72 μm; 95% CI, 50.14-65.31; P<0.05) and lowering the concentration of plasma homocysteine (MD, -3.66 μmol/l; 95% CI, -5.44--1.87; P<0.05; I(2), 87%). There was no significant change in the response to end diastolic diameter, glyceryl-trinitrate diameter, heart rate, baseline and peak hyperemic flow and systolic and diastolic blood pressure between the folic acid and placebo groups (P>0.05). Therefore, the meta-analysis indicated that 5 mg folic acid daily supplementation for >4 weeks significantly improved FMD and lowered the concentration of plasma homocysteine in patients with CAD. However, more RCTs are required in order to confirm these observations.Experimental and therapeutic medicine 05/2014; 7(5):1100-1110. · 0.94 Impact Factor