Nitric oxide homocysteine

S-Nitroso derivatives of the biological thiols—glutathione, cysteine (115) and homocysteine—have been considered as bioactive intermediates in the metabolism of organic nitrates and the endothelium-derived relaxing factor with properties of nitric oxide. A simple, rapid and reproducible method for separating these thiols from their... 

Stuhlinger MC, et al. Homocysteine impairs the nitric oxide synthase pathway role of asymmetric dimethylarginine, Circulation 2001 104(21 ) 2569-2575. 

Normal endothelial cells modulate the effects of homocysteine by facilitating the S-nitrosilation of homocysteine by nitric oxide. The formed S-nitrosothiol adduct is a potent vasorelaxing substance [2,108]. So, when high levels of homocysteine occur, they may overcome or impair the endothelial capacity for NO synthesis. Endothelial cell damage may result from increased production of reactive oxygen species or from impaired production of nitric oxide [3,102]. In endothelial cells, total homocysteine reduces the levels of tetra-hydrobiopterin (BH4), relative to dihydrobiopterin (BH ), thereby creating a dysfunctional eNOS causing a reduced amount of nitric oxide [1,101],... 

D. Pruefer, R. Scalia and A. M. Lefer, Homocysteine Provokes Leukocyte-Endothelium Interaction by Downregulation of Nitric Oxide, General Pharmacology 33 (1999) 487-498. 

Fig. 5.3 Chemical structures of nitric oxide synthase inhibitors. Mj-nitro-L-arginine (L-NNA) (a) 5-[2-[(l-iminoethyl)amino]ethyl]-L-homocysteine (GW274150) (b) A-[3-(aminomethyl)benzyl] acetamidine (1,400 W) (c) AG-monomethyl-L-arginine (l-NMMA) (d) 7-nitroindazole (7-NI) (e) aminoguanidine (f) A6-iminoethyl-L-lysine (L-NIL) (g)...

Jenkins, D.J.A., Kendall, C.W.C., Marchie, A., Parker, T.L., Connelly, P.W., Qian, W., Haight, J.S., Faulkner, D., Vidgen, E., Lapsley, K.G., and Spiller, G.A., Dose response of almonds on coronary heart disease risk factors Blood lipids, oxidized low-density lipoproteins, lipoprotein (a), homocysteine, and pulmonary nitric oxide A randomized, controlled, crossover trial. Circulation, 106, 1327-1332, 2002. 

Figure 3.2 Beneficial effects of folic acid on vascular wall. Folic acid circulates in human body as 5-methyltetrahydrofolate (5-MTHF). 5-MTHF lowers circulating homocysteine (Hey) levels, thus reducing systemic oxidative stress and Hcy-induced activation of prothrombotic mechanisms. In addition, vascular 5-MTHF has a favourable effect on intracellular Hey metabolism, attenuating Hcy-induced activation of NADPH oxidase isoforms (NOXs) in the vascular wall. Furthermore vascular 5-MTHF scavenges per se peroxynitrite (ONOO ) radicals in the vascular wall preventing the oxidation of vascular tetrahydrobiopterin (BH4) associated with endothelial nitric oxide synthase (eNOS) uncoupling and diminished vascular nitric oxide (NO) bioavailability. In total through these effects 5-MTHF lowers vascular oxidative and nitrosative stress. Thus by modulating vascular redox, 5-MTHF inhibits activation of proinffammatory pathways which orchestrate vascular wall inflammation and perpetuate endothelial dysfunction and atherogenesis development (unpublished).

Stuhlinger, M.C., Tsao, P.S., Her, J.H., Kimoto, M., Balint, R.F., and Cooke, J.P., 2001. Homocysteine impairs the nitric oxide synthase pathway role of asymmetric dimethylarginine. Circulation. 104 2569-2575. 

Li J, Zhang Y, Yao X, et al. Effect of homocysteine on the L-arginine/nitric oxide synthase/nitric oxide pathway in human platelets. Heart Vessels 2002 16 46-50. 

Fig. 17.5 Effect of nitric oxide on the synthesis of methionine and S-adenosylmethionine and methylation reactions. NO inhibits methyltetrahydrofolate reductase (MTR). This results in a decrease in tetrahydrofolate (FH4) and methionine. Additional reduction in the FH4 level may occur by the NO-induced oxidation of ferritin, a compound that inhibits the proteasomal degradation of FH4. NO affects SAM synthesis not only by inducing a decrease in methionine synthesis but also by directly inhibiting the liver-specific methyl-thioadenosyltransferase I/III (MATI/III) isozymes. The fall in SAM level cannot be fully compensated by an increase in the extrahepatic isozyme MATH, since this enzyme is inhibited by its reaction product. The reduction in homocysteine utilization for methionine synthesis may result in homocysteine accumulation. This probably does not lead to a consistent rise in cystathionine and reduced glutathione synthesis, dne to a reduced stabilization of cystathionine P-synthase (CBS) by SAM. Consequently, an inciea.se in SAH, associated with a decrease in the SAM/SAH ratio, inhibits methyltransferases (MT) and DNA methylation. The reduction in SAM level may decrease IicBa activation, thus favoring NF-kB activity...

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