coincides with a reduction in NO-stimulated sGC activity本文来自辣.文,论-文·网原文请找腾讯32.49114
Figure 1. NOS-dependent mechanisms of S-nitrosylation. Three principal [22].TwocysteineresiduesinthesGCa/bheterodimerare
mechanisms for regulation of NO synthase (NOS)-dependent protein S-
the targets of S-nitrosylation, C243 of the a-chain (aC243)
nitrosylation and the (patho)physiology associated with the induction or
and C122 of the b-chain (bC122). Of these, bC122 is in
disruption of these mechanisms are shown. (a) Binding of a transcription factor
(TF) to the NOS promoter induces expressionof the gene encoding NOS.(b) Influx proximity to the heme-binding site, although mutation of
2+ 2+
into the cytosol of extracellular or internal store-derived Ca promotes Ca -
either residue partially prevents SNO-induced sGC densi-
calmodulin (CaM) binding and activation of eNOS and nNOS (left). Alternatively,
tization [22]. These effects of NO/SNO are essentially
phosphoinositide-3 kinase (PI3K) activates protein kinase B (Akt), which
phosphorylates and activates eNOS (right). (c) Subcellular compartmentation recapitulated in cellular and animal models of nitrate
(co-localization) of NOSand itssubstrates,whichmightinvolvea directinteraction
tolerance and, in addition, partial sGC denitrosylation
(as in the illustrated case of a membrane-intercalated ion channel), is an important
and restoration of sGC activity are observed after treat-
determinant of the target specificity of S-nitrosylation and dysregulated co-
hindi sms http://www.hindisms-hindi.com/ localization can result in hyper- or hypo-S-nitrosylation. I/R, ischemia/reperfusion. mentwithN-acetylcysteine(NAC) [23]. Thus,denitrosyla-
tionofSNO-sGCmightunderliesomeoftheclinicalbenefit
of NAC therapy for nitrate tolerance.
childhoodasthma[18].Finally,pharmacologicalinhibition Therapy with the NO donor isosorbide dinitrate (in
of arginase leads to increased SNO levels in bronchial combination with hydralazine) markedly reduces
epithelia of allergen-challenged mice and, although it mortality in African-Americans with heart failure [24].
hindi sms http://www.hindisms-hindi.com/
can also increase inflammation [15], arginase inhibition Morbidity and mortality in heart failure patients result
correlates with protection fr本文来自辣.文,论-文·网原文请找腾讯324.9114 om allergen-induced airway from either arrhythmia or ventricular dysfunction that is
hyperresponsivity(AHR)inseveralasthmamodels[16,19]. due, at least in part, to downregulation of b-adrenergic
ThesedatasuggestthatalteringNOhomeostasisandSNO receptors (b-ARs) and dysregulation of calcium homeosta-
levels might ameliorate the asthmatic phenotype. sis. It is therefore of interest that NO bioactivity has been
NOorlow-molecular-weightSNOscanalsobeproduced strongly associated with both arrhythmia and pump
pharmacologically from organic nitrovasodilators, chief failure [25–27] and recent studies support the possibility
among which is nitroglycerin (glyceryl trinitrate; GTN). that S-nitrosylation of cardiac proteins ameliorates heart
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