Posted on Authorea 13 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159466811.11591709 — This a preprint and has not been peer reviewed. Data may be preliminary. ilrve ffcso noeosa ela xgnu Oo rti -irslto,apost-translational activity. a biological S-nitrosylation, protein we protein on context, on this effects In wide-ranging NO Oxide with treatment. exogenous Nitric NO, PPHN as with for well used reaction as regularly from dose endogenous arising inhalational modification of www.clinicaltrials.gov, the effects per times patients review 9 enrolling as currently will trials high clinical as 8 citing in some studied COVID-19, in cGMP failure vasodilator synthesis ratory activity protein the anti-Coronavirus and increasing having RNA of pulmonary with as action interfering persistent described primary for also its notably is on hypertension, NO based pulmonary (PPHN), for newborn therapy the established to of an hypertension (GTP) is triphosphate (iNO) guanosine NO converting Inhaled (sGC), cyclase (cGMP) guanylate monophosphate soluble guanosine airway- activates 3’,5’-cyclic turn cells, and in repair inflammatory which tissue NO, neurotransmission, cells, hemostasis, epithelial angiogenesis, smooth toward responses, by apoptosis respectively immune endothelium to and produced contributes epithelium and from is diffusion muscle; by tone (NO) vascular and oxide airway cells regulating nitric endothelial vascular and tract, neurons innervating respiratory in the environment, In redox with dose word and 202 source = NO of intersection including the nitrosylation nitrosylation. nitroso- of discuss protein including effects of and proteins, pathological effects SNO enzymes; and the vasodilation, of determining vasodilator hypoxic roles critical through physiological of flow the pathways blood inhibition review We of denitrosylation autoregulation and SNO-proteins. and propagated nitrosylation of hemoglobin also Redox-based equilibrium but targets. the controlled, interactions protein enzymatically regulate protein downstream reversible and on dynamically tar- compartmentalized impacts of and modification significant tightly transnitrosylation selective post-translational with is non-enzymatic This residues, the formation by surrounding cysteine. is (SNO) of recently of S-nitrosothiol which sequence chain been acid/base S-nitrosylation, function. side the has and protein thiol on the and on based review, to cysteines neonates, NO this group specific In exogenous in monoxide gets COVID-19. nitrogen and especially to a endogenous due hypertension, of syndrome of attachment pulmonary distress covalent effects respiratory for acute the therapy and summarize failure established we respiratory mus- an hypoxic smooth of is synthases relaxing treatment cGMP, oxide for NO generate nitric proposed to by Inhaled cyclase produced guanylate NO soluble Endogenous cells. of tone. cle activation airway including and cascades, vascular signaling of multiple regulator regulates comprehensive a is (NO) oxide Nitric Abstract 2020 13, July 2 1 Bhatia Vikram Consequences Biological Nitrosylation Oxide: Protein Nitric of Inhaled of Path the Tracing nvriyo aioaCleeo Medicine Manitoba of of College Institute Manitoba Research of Hospital University Children’s Manitoba of University 2 ircoiesnhs NS aaye h ovrino -riiet -irliegenerating L-citrulline to L-arginine of conversion the catalyzes (NOS) synthase oxide Nitric . 1 aaElnagary Lara , 1 n haaaDakshinamurti Shyamala and , 6 N a eetybe rpsdfrteteto yoi respi- hypoxic of treatment for proposed been recently has iNO . 3 . 1 tfntosa opeesv hsooia modulator, physiological comprehensive a as functions It . 1 nvitro in 5 niiigtevrlrpiaincceby cycle replication viral the inhibiting , 2 4 . Posted on Authorea 13 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159466811.11591709 — This a preprint and has not been peer reviewed. Data may be preliminary. rnfre otetre ytiefo te rtis(emdpoenasse rnntoyain,o en- or transnitrosylation), reactions protein-assisted metalloprotein-catalyzed moieties (termed or nitrosyl proteins by S-nitrosylase other NO, of to from activity motifs cysteine through redox-active target zymatically of the exposure by to formed transferred are (R-SNO) non-enzymatic proteins largely S-nitrosylated enzymes’ Donors being kinase and in by Substrates unique determined regula- Nitrosylation is is nitrosylation spatiotemporal Nitrosothiols: cysteine phosphorylation strict targets, serine/threonine and protein of their specificity, specificity for substrate the selectivity exhibit while However, modifications signaling Both tion. cell acts for nitrosylation phosphorylation. only suitable but manner with interactions; reversible protein-protein rapidly or hydrophobicity a stability, in protein alter can these glutathionylationof include Others ceptible. nitrosylation thiol Reversible regulation redox differentiation and pathologies growth, stability of cell number protein regulation, transcriptional to repair, apoptosis, damage and DNA from ranging processes biological (NO dioxide nitrite nitrogen species to reactive oxidized more be far the can to NO oxidized tissues, further or aerobic NO active; adjacent; In ( biologically is less protein water. are lose that of which if can anions, only presence NO protein in ); a nitrite nitrosylate 1 to to (Figure group (NO states thiol redox a cation with different ( nitroso react into electron become morph unpaired can to one but electrons with concentrations, or radical physiological complexes free at metal-NO reactive a species, as NO exists oxidized NO other or nitrate) (R-SNOs) dietary nitrosothiols (SNO) from protein S-nitrosothiol derived a usually form itself endogenous, to or NO sulfur-hydrogen signaling acid than a amino containing cellular stable group cysteine sulfhydryl more precisely the a organic is and reversible an on and ‘nitrosylation’ rapidly thiol, (-SH), both term the NO, is bond to the modification) attaches of covalently this nitrosation; NO of concentration is where function biological targeted, term local the chemical describe and to (proper used duration S-nitrosylation commonly seconds on Protein 3-5 depending affected. of (100 pathways half-life harmful, area measured a wide messenger or with physiological a beneficial 10-100nM, locally-acting over ranges short-lived, concentration diffusing a NO of as tissue function capable to gas cells lipophilic neighboring a is NO ytieSntoyainsre samdao fN-eae iatvt,bt nNScnann el n fol- and cells NOS-containing in signaling both intercellular bioactivity, for NO-related diffusion of NO mediator lowing a folding as protein serves S-nitrosylation correct (1.0%) Cysteine for domains critical bonds cytosolic disulfide than of enzymes formation (3.2%) redox the (1.6%) extracellular in proteins intracellular role in purely structural active versus common redox (3.5%) group proteins and thiol more transmembrane the acidic in at and nucleophilic, greater likely is more is reactions residues which transfer cysteine conserved chain, electron of most side making the thiol orbitals, of hybrid reactive one of highly but presence its proteins, in to residues due abundant unique least the among is Cysteine formation S-nitrosothiol promote S-Nitrosylation greatly Cysteine that reactions order first driving concentrations, S-nitrosothiol in with recombined (RS radical thiyl RS a (thiolate, to protonated is S-nitrosothiol thiol form that if but thiol; * NO 2 ,dntoe roie(N trioxide dinitrogen ), - a entoyae yN by nitrosylated be can ) 23,24 8 * h eo niomn around environment redox The . O ohRS Both NO. n euaepoenpoeninteractions protein-protein regulate and , 15 hsrato sfclttdb rsneo ueoieain(O anion superoxide of presence by facilitated is reaction This . 28-31 . 11 32,33 N a rs rmedgnu reoeosN,fo irt (exogenous nitrite from NO, exogenous or endogenous from arise can SNO . 12 2 - O . n RS and sntteol ottasainlmdfiaint hc ytie r sus- are cysteines which to modification post-translational only the not is 3 ,o eoyirt (ONOO peroxynitrite or ), + * 2 rgi lcrn obcm irxlain(NO anion nitroxyl become to electrons gain or ) O 34 ilratwt ONOO with react will 3 carbonylation , 26 omdb xdto of oxidation by formed vr30 rtisaergltdb irslto,impacting nitrosylation, by regulated are proteins 3000 Over . * Obcmsciia when critical becomes NO 2 38-41 27 * O u ihu lcrclcag.I sntvery not is It charge. electrical without but NO) * yrgltdSntoyaini mlctdi a in implicated is S-nitrosylation Dysregulated . by ) 35 nti,ntoyainsae iia properties similar shares nitrosylation this, In . 25 guanylation , . * - ) NO - 14 oi rdc of product toxic , μ . * ) oigfel cosmmrnsof membranes across freely moving m), 2 Oisl ecssol ihaneutral a with slowly reacts itself NO , * 9,10 Ooiie yoye oNO to oxygen by oxidized NO * Owl ec ihi eyrpdyto rapidly very it with react will NO ilgclyatv intermediate active biologically a , 36 21 n sulfhydrylation and ytie lyaprincipal a play Cysteines . * Oi npharmacological in is NO + 8 Osgaigcnprove can signaling NO . 7 * 42,43 22 ilpopl hydrolyze promptly will nbooia systems, biological In . Owt O with NO 2 rmt aayi by catalysis promote , 2 - ) - 17 nnon-enzymatic In . 16 rntae(NO nitrate or ) ti functionally is It . 14 19 eue thiol reduced A . . h frequency The . - ) 13 18 2 NO . 37 - u othe to due resulting , Several . 10 2 . then , + can 3 20 - ) , Posted on Authorea 13 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159466811.11591709 — This a preprint and has not been peer reviewed. Data may be preliminary. h te ao euao fteclua rti ho eo tt stirdxn(r) ubiquitously a (Trx), thioredoxin diverse is of denitrosylation state the substrates redox mediate directly protein thiol thioredoxins and mitochondrial R-SNO protein and ion cytosolic nitrosylation cellular superoxide GSNO, protein for increases the specificity limits that of which state oxidoreductase regulator redox conserved cellular major GSH the circulation other reduced proposed systemic in of The a the levels imbalance to with decreasing an by NO consistent equation, S-nitrosylation, eNOS-derived is the promotes pulmonary of peroxynitrite resistance of activity side vascular the other systemic conveying the decreased in GSNO with promoting for by associated role proteins, is S-nitrosylated deletion of GSNOR level substrate cellular vasodilation a the temic is regulates GSNO indirectly denitrosylation residues. GSNOR GSNO cysteine nitroso of denitrosylated the levels on GSH takes it groups increased which reverts –SH (GSH) which free glutathione GSNOR, leaving reduced for GSNO, by become catalyzed to is group proteins ammonia nitrosylated to of reduced Denitrosylation ultimately is which system intermediate, NADH- N-hydroxysulfenamide respiratory ubiquitous conserved, glutathione the enzyme evolutionary dehydrogenase an in (GSNOR), alcohol R-SNO reductase GSNO dependent relevant by physiologically regulated nitrosoglutathione, is most to state the nitrosylation glutathione is carriers between SNO (GSNO) equilibrium intracellular S-nitrosoglutathione an other and by or NO, reductase, determined by thioredoxin triggered be to nitrosylation can thioredoxin protein denitrosylation between proteins balance to S-nitrosylated the lation of reflects denitrosylation NO enzymatic of the pool cellular the Thioredoxin of Turnover and GSNO Denitrosylation: of Regulators CysNO as radical NO such releasing species by stabilityble proteins NO or release their spontaneous peptides, in can stable acids, vary possible more amino smallest R-SNOs is thiol-containing the larger, as late acid, slightly chemistry, (thionitrous (GSNO), HSNO R-SNO S-nitrosoglutathione than characteristics R-SNO); determines different R exhibits structure the trosocysteine) amino of surrounding the nature of analysis The computational by predicted be can modifications sequence cysteine enzymatic given acid or a redox-dependent of nitrosylatable cysteine nitrosylation other these for by that between sity targeted overlap of cysteines little those S-nitrosylation is and the there cysteines, direct transnitrosylation; that site-specific interfaces guides micro-environment protein-protein His) Arg, for re- (Lys, sites basic environment may provides and subcellular which Glu) that base), (Asp, in acidic a ity by and flanked immediately acid acids structure pocket, sequence an amino hydrophobic a quaternary a (generally or candidate: interactions, in residues nitrosylation tertiary sitting protein a nucleophilic residues protein’s close as of the by cysteine consisting from particular regulated a acids sult or is Not marking amino Nitrosylation albumin motifs” next. adjacent “SNO a S-nitrosylated. like and of of get next presence proteins a can the triggers by large protein event and nitrosylation a of one in whereby residues cascade, cysteine signaling cysteine/ every cysteine kinase a transnitrosylation (eg to to in proteins similar intermediates anchored cascade weight as are function molecular R-SNO. which groups new low nitrosoglutathione) a involve S-nitroso creating 10% configuration, all acid hemoglobin, of amino surrounding 90% correct the While with protein nearby a on cysteine (NO nitroso the transnitrosylation, 54,56 . 46,47 49 . h urudn eiusdtriecsen -irslto,b leigtilnucleophilic- thiol altering by S-nitrosylation, cysteine determine residues surrounding The . 64,65 63 n SO-ulmc aeicesdbodlvl fSntoyae proteins S-nitrosylated of levels blood increased have mice GSNOR-null and , hraooia niiino eei eeino SO ed oehne sys- enhanced to leads GSNOR of deletion genetic or inhibition Pharmacological . 19 54,55 hoeoi’ y---y ciesite active Cys-X-X-Cys Thioredoxin’s . 13 h irs ru a lomv rmsal -irspoen ols sta- less to S-nitrosoproteins stable from move also can group nitroso The . hc ntr a o-nyaial eops ocsen n nNO an and cysteine to decompose non-enzymatically can turn in which , 61 45 + ic SOi hsi qiiru ihohrSntoyae proteins, S-nitrosylated other with equilibrium in thus is GSNO Since . ru are yadnrRSOi rpe noa cesbetarget accessible an onto dropped is R-SNO donor a by carried group ) h rsneo hre eiusi h iiiyo ytieresidue cysteine a of vicinity the in residues charged of presence The . 61,62 SO eaoie SOt xdzdguahoepu a plus glutathione oxidized to GSNO metabolizes GSNOR . 3 45 57,58 rtoi nlssrva irsltdcysteine nitrosylated reveal analyses Proteomic . 68,69 h ellrblneo rti transnitrosy- protein of balance cellular The . ncnrs oGNRssrc substrate strict GSNOR’s to contrast In . 52,53 70 S 59 ake eirslto samulti- a as denitrosylation tackles + 44 -irstil a transnitrosy- can S-nitrosothiols . ntooytie glutathione/ -nitrosocysteine, Fgr ). 2 (Figure rnntoyaincncet a create can Transnitrosylation . rNO or 66,67 . - oerpdyta they than rapidly more , 50,51 44 48 . 10 yN (ni- CysNO . hsprotein This . h propen- The . 44 19 60 That . On . Its . S - Posted on Authorea 13 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159466811.11591709 — This a preprint and has not been peer reviewed. Data may be preliminary. eltpso elcmatet ntecus fterpamclgclaction. many NO pharmacological in within their Generating proteins of proteins Nitrites of course nitrosylation and of the cause Nitrates nitrosylation may in which compartments targeted NO, control cell the of target or residues sources fine permits types exogenous Such cysteine cell discussing NO activation. when multiple NOS endogenous reported with of regions not of associated is different temporally S-nitrosylation case and to the in spatially bind compartments, in resulting can subcellular proteins isoforms effect cytoskeletal caveolar protein, NOS of or of target different localization depolymerization nitrosylation isoforms; same actin alter NOS the among thus stress; of targeting and sheer NO, cysteine activity as of of amount eNOS such selectivity is greater stimuli alter body a mechanical can Golgi releases to reorganization caveolae the respond membrane Golgi on can at in activation eNOS eNOS eNOS while Consequently, to agonists, agonists. compared Akt-dependent membrane to where or caveolae plasma responsive membrane calcium-dependent less to in by and body activated Golgi; Golgi efficiently the from within complexes proteins trafficking signaling of granule receptor nitrosylation regulate enhances may that through nitrosylation pool or adjacent NO proteins directly local those a substrate, S-nitrosylation to S-nitrosylation nitrosylation their confining promote their targets localized region, SNO to and creates of eNOS, enzymes NOS proximity to physical of NOS The compartmentalization between proteins interaction to proteins. scaffolding specific favors due of NOS concentration S-nitrosylation its to the diffusible, to conducive freely environments is NO Though NO. additional of or radicals thiyl Hsp90 proteins and including NO of NO local between S-nitrosylation high reactions activity range metals for involves A their transition required S-nitrosylation micromolar by isoforms. where be low catalyzed NOS sufficient to is other be the thought may do in is levels than oxygen, NO are NO lower of of concentrations presence concentrations SNO in local concentration, endogenous higher generates NO, NOS of Inducible amounts levels important physiologically physiological in At NO eNOS generating of not output though NO eNOS, the expresses stabilizing stress calcium-independently Hsp90, sheer protein phagocytes lung and heat-shock of nNOS and exercise burst gut calcium. respiratory by liver, the intracellular lium kidney, to by in contributing NOS stimulated also response, by expressed, inflammatory neurons, produced constitutively in is are found NO nNOS is Endogenous and eNOS NOS3). (eNOS; compartments. NOS L-arginine endothelial substrate its and from NOS2) (iNOS; homeostasis NOS oxygen inducible to linked tightly enzymes is (NOS) NO intracellular activity of redox Generation the Nitrosylation modulate Compartmentalized reciprocally and can NO NO Endogenous itself stress. thioredoxin nitrosative nitrosylating ameliorating by reduced in of thioredoxin, finally as variant of well is oxidized HNO as site of an signaling active release HNO forming NO thioredoxin causing (ii) the cysteines, bridge, site substrate, (iv) disulfide active (TrxR) and target thioredoxin’s the reductase substrate, its resolves reduced thioredoxin and cleavage, now cysteine thioredoxin by heterolytic the reactive between by releasing second bridge cysteine and the R-SNO’s disulfide thioredoxin the (iii) mixed from released, a NO of is displaces formation cysteine in nucleophilic the resulting (i) process: step 90,91 76 92 Omdae irslto feO sfloe ytasirslto feO regulators eNOS of transnitrosylation by followed is eNOS of nitrosylation NO-mediated . h he sfrso O nmmainclsicuenuoa O nO;NOS1), (nNOS; NOS neuronal include cells mammalian in NOS of isoforms three The . niiigteatvto feO nangtv edakmcaimlmtn production limiting mechanism feedback negative a in eNOS of activation the inhibiting , 93 nedteilcls irslto agtpoen r yial on ncoeproximity close in found typically are proteins target nitrosylation cells, endothelial In . 27,77 97,98 88,89 O sfr xrsindffr cosogn,tsus el,o subcellular or cells, tissues, organs, across differs expression isoform NOS . aelreO loclclzswt otclatnfiaet,s eNOS so filaments, actin cortical with colocalizes also eNOS Caveolar . 71,72 78 n ycrnchypoxia chronic by and , ahNSioomcnas eSntoyae,wihdown-regulates which S-nitrosylated, be also can isoform NOS Each . agtRSOpoen a lodrcl rnntoyaeoeof one transnitrosylate directly also can proteins R-SNO Target . 94 h Ognrtdb NSrmiswti t subcellular its within remains eNOS by generated NO the ; 74 . 4 78 96 acu-nestv NSi nue uigthe during induced is iNOS Calcium-insensitive . 73 -irslto fpoen nteGlireduces Golgi the in proteins of S-nitrosylation . 95 96 hoeoi ly natv oei attenuating in role active an plays Thioredoxin . NSi on nteGlibd,generating body, Golgi the in found is eNOS . h NSlctda h lsaem is plasmalemma the at located eNOS The . 80 hc lourgltseO’ chaperone eNOS’s upregulates also which , 75 rmrl ynti xd synthase oxide nitric by primarily , 79 NSi nue nendothe- in induced is eNOS . 82 . 81 mohmsl also muscle Smooth . 100 99 hsprofound This . hr salso is There . 86,87 though , 60,83-85 . Posted on Authorea 13 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159466811.11591709 — This a preprint and has not been peer reviewed. Data may be preliminary. ie ftrsn irto eetkna h rmr as ftsu nuy hswudipyiOdecreases iNO imply would this injury, tissue of cause primary the hyperoxia as of taken toxicity were the nitration tyrosine If sine. 12 within 5ppm of concentration a reach hour can 1 O lung, toxic than 100% at the more in reported iNO takes to 20ppm are reaction toxic with nitrosylation, directly treatment above or more during doses nitration derivative min by relatively protein at NO circulation a including reactive observed considered systemic level, the been 20ppm, cellular the has a to to doses methemoglobinemia, at up lower or primarily toxicities doses (iNO), However toxicity, iNO inhalation apparent use 80ppm. titrated clinically regimens by treatment range; lungs current safe the Most to nitrites. delivered vasoactive is NO Exogeneous increasing further NO without Exogenous S-nitrosocysteines circulating of formation vasodilation increases NaNO pulmonary oxide for nitric agent with causative NaNO treatment the of is that NO forms improving than formation or acidified effects nitration pressure of vasodilator protein arterial greater nebulization causing have pulmonary contrast, without decreasing albeit in without NO, oxygenation; vasoconstriction inhaled pulmonary does hypoxic than lung inhibits extent the in greater content a R-SNO to increasing also while NO, with haled patients NaNO hypertensive subcutaneous pulmonary pups, hypertension in pulmonary resistance hypoxic vascular chronic of NO inhaled models pulmonary as PPHN without well or in NO as tive with vasodilator least infants at pulmonary in rats acute lower neonatal significantly effective are an levels is nitrite adults Serum with compared NO. hypertension, generate NO to in NOS NO poor on circulating are hypoxia, of sources by majority tritional potentiated the is adults, reductase In Nitrite formation. SNO to vasodilation thence enzymatic NO contributing of endogenous and need dehydrogenase NO, so aldehyde of without of mitochondrial treatment rapidly pool of for NO tive aid drugs releases the with SNP NO-releasing (NO NO isosor- anion used releases disease. congener commonly nitroglycerin acting artery while are long coronary catalysis, its (SNP) and Nitroglycerin, nitroprusside hypertension donors. sodium systemic NO platelet and as of inhibition use dinitrate, and therapeutic vasodilation bide their including NO, in free resulting of aggregation, reminiscent responses physiological elicit Nitrites eetvl nrae irto,dsaorn irslto;btadto f2pmiOlmt h nraein increase the limits iNO S-nitrosocysteine ONOO 20ppm of of with nitrosylation. formation addition and enhancing but nitration while nitrosylation; protein nitrotyrosine disfavouring between nitration, balance the increases in selectively O introduced, nitration, 80% is tyrosine to iNO protein when Exposure as occurs, ni- shift manifest downstream a to However its known is of toxicity ONOO nature of degradation oxygen the action Alone, the determines to due iNO ). largely 1 and environment (Figure oxidative chemistry modes trosative high-frequency the of between use interaction during The airways distal in stasis gas about * NO 2 - 2 ae hrp ihrltvl oetploayvsdltreeti h etn fexperimental of setting the in effect vasodilator pulmonary potent relatively with therapy based 2 116 cuuainwti h iwy uigiOtetet huhteehsbe oeconcern some been has there though treatment, iNO during airways the within accumulation - 119 102 srdcdb icltn rtsu on irt xdrdcae ocet tbe nonreac- stable, a create to oxidoreductases nitrite bound tissue or circulating by reduced is ) - oiiyi oedpnetadagetddrn xdtv tes irgndoie( dioxide Nitrogen stress. oxidative during augmented and dose-dependent is Toxicity . oproduce to hsfidn a enwl ecie nhprxamdl fbocoumnr dysplasia bronchopulmonary of models hyperoxia in described well been has finding This . . 2 2 - ail nue ohtrsn irto n ytientoyain nraet 5 O 95% to Increase nitrosylation. cysteine and nitration tyrosine both induces rapidly spopl eue oN ftsu xgnlvl erae eutn nprotective in resulting decrease, levels oxygen tissue if NO to reduced promptly is 115 122 * NO uprigteter htSOi o tefaploayvasodilator. pulmonary a itself not is SNO that theory the supporting , 2 n nedvr ihdsso N r eotdt iiaeteltaiyo 95% of lethality the mitigate to reported are iNO of doses high very indeed and ; nrae iseN,aeirtn umnr yetnincmaal oin- to comparably hypertension pulmonary ameliorating NO, tissue increases 2 n NO and 117 3 - -103 irtrsn a edt nyeiatvto n loaclrt protein accelerate also and inactivation enzyme to lead can Nitrotyrosine . h s fcniuu-o etlto icishslreyeliminated largely has circuits ventilation continuous-flow of use The . 104 eutn nlwrcneso oNO to conversion lower in resulting ramn ihihldehl(ly)ntie oaieNO volatile a nitrite, (alkyl) ethyl inhaled with Treatment . 2 2 - eutn ndcesdONOO decreased in resulting , - 2 alone - 106 sdrvdfo itr irt (NO nitrate dietary from derived is ytmco nae oimntie(NaNO nitrite sodium inhaled or Systemic . 114 2 tigrdvsdlto.Nblzto fLcsen during L-cysteine of Nebulization vasodilation. -triggered ugsigi steN ees n o ipyteSNO the simply not and release NO the is it suggesting , 2 n t8pmiOwti i;wiei 1 O 21% in while min; 3 within iNO 80ppm at and , 107,108 5 105 n rvnshprxaidcdln nuyin injury lung hyperoxia-induced prevents and , 110 euie NaNO Nebulized . 121 NaNO . β- hsi srbdt h xesN reacting NO excess the to ascribed is This . thalassemia 2 2 118 nuehge eeso Oadthus and NO of levels higher induce nrae ugN n N contents SNO and NO lung increases . - 2 -104 vial o ecinwt tyro- with reaction for available 109 2 n hsgetrdependence greater thus and ncrnclyhpxcrat hypoxic chronically In . ctl eue pulmonary reduces acutely 3 - ,wiei ents nu- neonates, in while ), 111-113 euie NO Nebulized . 2 sa alterna- an is ) 101 2 Nitrite . - * donor, NO 2 this 120 2 2 ), 2 - . Posted on Authorea 13 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159466811.11591709 — This a preprint and has not been peer reviewed. Data may be preliminary. h ocnrto fO of concentration the CO O pendent, with O readily CO and reacts with NO NO O of reaction species. if rapid oxygen its reactive so with by do NO will of combination but formation of ONOO R-SNO rate glutathione, promote the or to on sufficient cysteine depends be may nitrosylating process of this quantities, capable not NO are with NO of solutions O in ahrta eeaigONOO O ONOO generating by than peroxidation rather lipid tions direct inhibit NO of concentrations mod- protein primary the alveoli is and nitrosylation airway tension, in oxygen seen concurrent ification of regardless present coadministration administration, is by iNO toxicity relieved After dysfunction, nitrosocysteine surfactant that and suggesting inflammation dismutase, causes superoxide hyperoxia of with NO dose high irt euts,pouigfo NO leading from R-SNO, low-molecular-weight producing a nitrosylated reductase, as a plasma nitrite releases the a nitrosohemoglobin to also cells deoxygenation, but vasodilation blood upon hypoxic hemoglobin, red and to from oxygenated from equivalent, that exported oxygen NO is proposed: in of a which been intermediate role as dissociation have mechanisms SNO putative in Two carries its results circulation flow. blood The tissue of blood increasing demand. hypoxic because vasodilation, metabolic a localized largely to triggers to delivery modification, hemoglobin oxygen beneficial oxygenated tissue a couples of which as vasodilation, Hemoglobin? viewed hypoxic of be mediating Nitrosylation may or formation Reduction Nitrosothiol Nitrate Vasodilation: Hypoxic O and with modification. that NO NO post-translational assumed other of be any can kinetics than it reaction more concentrations, the oxygen formation high circumstances, therapeutic both with under combination in microcirculation patients, the hypoxemic in NO to nitrosylation of protein bioavailability cell decreases endothelial activity increase dismutase to sufficient is hypoxia Acute dismutase iNO. O superoxide diffusible from of directly excess formed an of presence in O channels not but anion formation; via SNO membranes compartmentalize cell effectively traverse can they though rGN yrlsst yN-lcn,wihetrclsvateLtp mn cdtransporter acid amino L-type the via cells enter which CysNO-glycine, transporter to via dipeptide or hydrolysis spontaneously GSNO either or NO, H airway, free transnitrosylate isomerase can release disulfide including R-SNO protein to circulating locations, surface decompose distal cell may by R-SNOs in catalysis So R-SNO Dissociation intracellularly. of occurs group. spaces formation NO signaling the measurable extracellular of the and release conformational by in gut the accompanied of results delivery lungs, is Upon hemoglobin the nitrosohemoglobin of S-nitrosohemoglobin. in of forming deoxygenation molecules cysteine, tissues, with hemoglobin the reaction to to NO oxygen permits bound subunit is beta oxygen the of when change paradigm, NO SNO-Hb plasma the circulation of venous In nitrosohe- decline the of venous gradient in to a S-nitrosothiols arterial hypothesis plasma SNO-Hb the in the hypothesis, increase of case an in with gradients, moglobin, arteriovenous of observations from arise 2 2 2 exposure - - reydffs cosmmrns ste none neegtcbrira h yrpoi ii bilayer, lipid hydrophobic the at barrier energetic an encounter they as membranes, across diffuse freely omto sahlmr oho yeoi n yoi umnr niomns ntefre case former the in environments, pulmonary hypoxic and hyperoxic of both hallmark a is formation - hc ilidc ho irslto;bti ioteratvt fONOO of reactivity the vivo in but nitrosylation; thiol induce will which , 126 Oatoiaint N to autooxidation NO . 123 2 2 isniiemechanism -insensitive - irscsen oiiy fpeet ed ob cone o eaaey diitainof Administration separately. for accounted be to needs present, if toxicity, Nitrosocysteine . eut n10fl oeecetgnrto fSOta osONOO does than SNO of generation efficient more 100-fold in results 134 149 2 138 - 2 ho xdto nrae shpxawresadctslcRSsrs increases stress ROS cytosolic and worsens hypoxia as increases oxidation Thiol . epciey yfclttn rnfro Oi h irs om eolbnfunctions hemoglobin form, nitroso the in NO of transfer facilitating By respectively. 132 prahseumlrwt O N omto nrae exponentially increases formation SNO NO, with equimolar approaches n/rta NO that and/or ; n ntelte u orsiaoyuncoupling respiratory to due latter the in and , 33,60,88,142,143 2 hc blse t irstv efficiency nitrosative its abolishes which 125 -130 2 noye-ihevrneti eurdfrSOfrain anaerobic formation; SNO for required is environment oxygen-rich An . 129 O h rfrnilfraino N siptd ete ONOO Neither imputed. is SNO of formation preferential the ; 3 N omto slna sN ocnrto nrae;btwhen but increases; concentration NO as linear is formation SNO . 2 2 olw eododrkntc,btweeN si pharmacological in is NO where but kinetics, order second follows - ognrt ebaeprebeHSNO membrane-permeable generate to S hl otRSOaemmrn-memal,vasodilatory membrane-impermeable, are R-SNO most While . OadN and NO , 2 - stecruaigN eevi,addoyeolbnat as acts deoxyhemoglobin and reservoir, NO circulating the is 144,145 6 2 2 O loigN iuinit h el Alternatively, cell. the into diffusion NO allowing , - u oisconsumption its to due , 3 hc as vasodilation cause which , 131 ne hsooia odtosti would this conditions physiological Under . 2 - - ugsigN rw O draws NO suggesting , ecie bv ol rv nitrosothiol drive would above described 127 137 h aeo xgnu Ofurther NO exogenous of fate The . 128 136 124 siOi sal administered usually is iNO As . otmoaeu generation Contemporaneous . eraei oa superoxide local in decrease A . 133 . 140 n ncs ftenitrate the of case in and ; n irtv niiinof inhibition nitrative and 141 - sdaaial modified dramatically is 146 . 139 - rsmlryCysNO, similarly or ; i ONOO a via , ohhypotheses Both . 2 - noohrreac- other into 2 127 2 spresent is - Higher . 147,148 oform to - inde- - 135 nor or . Posted on Authorea 13 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159466811.11591709 — This a preprint and has not been peer reviewed. Data may be preliminary. NO NO venous NO increases of cell- dose-dependently blood infusion red animal arterial of hypoxic loss an in no showed inhalation hemoglobin nitrite of following residue Cys93 vasodilation conserved hypoxic the dependent of mutation after ground gained NO of reductase tissues NO nitrite prime to to abundant a activity NO as vasodilator an it NO is reinstated of deoxyhemoglobin also NO transduction by for the reduction required intravascular for acidosis ready candidate its and NO vasodilator, hypoxia of intrinsic of concentration unlikely high degree the the and while oxidoreductase, delivery. paradigm, improves oxygen nitrite flow and transported the blood flow the In and blood where relax however, local vessels perfusion; modulating released, cerebral directly is decreasing tension, NO vessels, oxygen blood local contracts of S-nitrosohemoglobin sensor physiological a as pce nbet rce oteoye-eurn tpo ho irslto,rsligi oa pulmonary local in resulting nitrosylation, NO thiol or of NO step releasing oxygen-requiring without heme-nitrosyl the of ex- build-up cells; to a gas red proceed vasoconstriction causes for hypoxia transfused to sustained flow by unable to blood delivery exposure species matching; oxygen autoregulate perfusion renitrosylated to impairing ventilation is influence cells nitrosohemoglobin, hemoglobin to and its CO in blood when respiration oxygen, deficient red restored of is is permit gases: this picture to blood three a NO Stored of paints of physi- act paradigm change. activity in SNO-Hb balancing the predominate the a transduce may of as nitrosothiols one defense autoregulation but elegant flow hypotheses, recent exclusive blood A mutually not conditions. are ological paradigms nitrite and SNO-Hb ucersoss -irslto fGK niisitrcino R2wt deegcrcpos prevent- receptors, adrenergic with GRK2 internalization of and interaction phosphorylation inhibits receptor GRK2 ing of S-nitrosylation responses. muscle caspase- stress oxidative triggers transnitrosylation, O thioredoxin limits of homeostasis, means maintaining thioredoxin, apoptosis de- by of to transnitrosylation mediated also its reported denitrosylation, to is due caspase-3 thioredoxin denitrosylation of of mitochondrial whether state S-nitrosylation discern a change cells in protein. not to rests endothelial to does indeed difficult in protein SNO measured from signal often cumulatively swapped apoptotic is as is crease dangerous, It group or nitroso protective activity. the is protein while protein specific inhibit a or of activate nitrosylation may nitrosylation better. Endogenous always not Nitrosylation is Protein more of identical; Consequences be to NO assumed generate be to cannot methemoglobin nitrosylation reduce will NO deoxyhe- concentrations, of nitrosohemoglobin NO particularly high increases, At methemoglobin while moglobin. decreases, paradoxically hemoglobin of hemoglobin nitrosylation transnitrosylate to large well too as NO is hemoglobin GSNO while nitrosylate NO hemoglobin, can in of reacts residue ratio cysteine or buried the thiols the hemoglobin and NO nitrosylates concentrations, to preferentially oxygen oxidized NO and concentrations, O NO physiological with In local on hemoglobin. depends to hemoglobin of Transnitrosylation 2 - eutn nmteolbn ne oesai O homeostatic Under methemoglobin. in resulting , - a ea niao fedgnu Obtntisl c savasodilator a as act itself not but NO endogenous of indicator an be may 2 - 2 ag 5-00M hl icltn lsantoohosaeetmtdudr10nM under estimated are nitrosothiols plasma circulating while 150-1000nM, range 2 - – peetdwti e el yterecetsprxd imts ciiy,rte hnbeing than rather activity), dismutase superoxide efficient their by cells red within (prevented production 2 -152 165 saptnilsoaepo o O hr saltmr irt vial;cruaiglevels circulating available; nitrite more lot a is there NO, for pool storage potential a As . 2 159 -161 irslto a le eetrsaiiyo unvr leigara n aclrsmooth vascular and airway altering turnover, or stability receptor alter can Nitrosylation . 163 xeietlihlto fOntootao,agsta nue irstilformation nitrosothiol induces that gas a O-nitrosoethanol, of inhalation Experimental . 71 eti te irs oosaepsil;aogsalRSO,CsOcnaccess can CysNO R-SNOs, small among possible; are donors nitroso other Certain . hs h ffcso noeosN n xgnu Oo eeca hemoglobin beneficial on NO exogenous and NO endogenous of effects the Thus, . 164 loi nohla el,cntttv -irslto fNDHsbntp47phox subunit NADPH of S-nitrosylation constitutive cells, endothelial in Also . u nrae irslto fagns rgesuculn feO n worsens and eNOS of uncoupling triggers arginase of nitrosylation increased but ; 2 - 2 - rdcsn nraei lo o,wieeO ciainb acetylcholine by activation eNOS while flow, blood in increase no produces etrshmgoi irslto,adas umnr vasodilation pulmonary also and nitrosylation, hemoglobin restores , 153 leito fploayhpreso n teuto fremodeling of attenuation and hypertension pulmonary of Alleviation . 62 nasneo xgn h Obudt eolbni eesdas released is hemoglobin to bound NO the oxygen, of absence In . 151 2 - eeswieagetn oa lo o,sgetn h measured the suggesting flow, blood local augmenting while levels hl lsacrlpamnat santiesnhs,oxidizing synthase, nitrite a as acts ceruloplasmin plasma while 39 u ope yai eel htwiectslccaspase-3 cytosolic while that reveals dynamic complex a But . 154 166 n ua subjects human and 2 hsaet ahpyai n oetae epne to responses potentiates and tachyphylaxis averts This . - 158 eurdt rv hsrato,iiilymd NO made initially reaction, this drive to required 7 150 nteploaycruain N-bi purported is SNO-Hb circulation, pulmonary the In . 2 . odtos fteN:brtoecesphysiologic, exceeds ratio NO:Hb the if conditions, 139 155 exmolbni kltlmuscle skeletal in Deoxymyoglobin . upr hshptei.However hypothesis. this support 2 n NO and 156 . 2 - 157 euto yxanthine by reduction 2 - hr intracellular where , ihu increasing without , 139 hsview This . 162 160 NO . . 2 - an 2 - Posted on Authorea 13 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159466811.11591709 — This a preprint and has not been peer reviewed. Data may be preliminary. nsm ytientoyaini oesai mlfiro Omdae aoiain rtco rmtoxic from protector a vasodilation, NO-mediated of amplifier homeostatic a with is interfering nitrosylation mechanisms, cysteine sum, similar G In by with pathways relaxant cyclase muscle adenylyl smooth activation. of enzyme major interface smooth both activation artery affects pulmonary the nitrosylation in at CysNO cyclase, to found adenylyl exposure reported are have following vasodilator, We and congener sGC. hypoxia, of the following activation muscle of allosteric NO-independent inhibition confer causing and nitrosylation NO, nitrosylation-damaged endogenous to a response reactivate sGC to sGC the developments of sensitivity 58-2667) Therapeutic (BAY NO. cinaciguat include to sGC unresponsive hypertension sGC, including angiotensin-mediated desensitized in proteins muscle cellular muscle smooth of smooth vascular S-nitrosylation treatment; increased NO causes reductase thioredoxin sGC of resistance inhibition NO causing system; therapy and iNO activity during catalytic occur sGC to known is nitrosylation sGC candidates sGC of in the Cys122 heterodimer of a assembly is and site cGMP- Hsp90 acts catalytic downstream (sGC) GTP activating cyclase Its thereby β GTP, guanylate vasorelaxation. from Soluble promoting cGMP and sGC ). generating (PKG) 3 NO, kinase (Figure protein for dependent inhibition receptor intracellular cyclase the guanylate as is muscle smooth vascular fSntoyainaelclzdt yokltnadE/og rnpr ytm euaigpoenfolding, protein regulating system, phosphorylation transport myosin ER/Golgi regulating apoptosis and targets and cytoskeleton as proliferation to spectrometry transduction, mass signal localized by are identified proteins S-nitrosylation CysNO, of with challenge muscle smooth vascular Following inflam- edema triggering pulmonary chemoattractant causing a nitrosylation becomes is nitrosylated, which when transporter, signaling protein-D, matory acid Surfactant effect L-amino damage. NO the local diminished by cause in mediated resulting is hyperoxia, hemoglobin by of fluid impaired lining transnitrosylation alveolar facilitate in to CysNO to CysNO cysteine of nitrosylation triggers iNO ihnteln,iOi rsneo bec fhprxacue ai rti irslto nara ep- airway in nitrosylation protein rapid endothelium causes nitrosylation vascular hyperoxia own in its of also by absence and inhibited or interstitium, alveolar presence and in ithelium iNO brain lung, worsening the increases, inhibition PTEN Within NOS regulator by survival ameliorated the is sepsis of in this nitrosylation mortality injury; ischemia, higher have hypoxic im- and after anesthesia nitrosylation reperfusion under of hypotension systemic reversal develop is proteins, while depression dysfunction myocardial nitrosylation, septic organ reverses protein mortality and GSNOR widespread and hypotension pressure and shock, blood induction septic proves In iNOS with consequences. associated negative carries nitrosylation Excess blockade receptor surface properties promotes VEGF endothelial fibrinolytic dynamin to or the of subject antiplatelet to nitrosylation increasing adherence hand, activator, neutrophil other plasminogen the tissue surface On cell dilator. and internalization constrictor receptor both agonists, adrenergic 1 uui,i rgesteisrino eemit,te iscaino the of dissociation then moiety, heme a of insertion the triggers it subunit, 188 α 1 eutn ntels fN-eitdatra relaxation arterial NO-mediated of loss the in resulting , and β 182,183 uui,adCs4,Cs1 in Cys516 Cys243, and subunit, β 1 190 uuis ahcnann heme-NO/O a containing each subunits, irslto fayoeo hs ytie eestzssCatvt oN stimulation. NO to activity sGC desensitizes cysteines these of one any of nitrosylation ; 177 ohcniin akdb nrae noeosN,aecmlctdb nitrosylated, a by complicated are NO, endogenous increased by marked conditions both , pteilN+canl Ea) rtclfrrgltn lelrfli,aeihbtdby inhibited are fluid, alveolar regulating for critical (ENaC), channels Na+ Epithelial . β 167 uui;o icga BY63-2521) (BAY riociguat or subunit; rtcieeet fedteilpoenntoyainicuentoyainof nitrosylation include nitrosylation protein endothelial of effects Protective . α 175 1 179 / 170 β 172 n yntoyaino s9,i rsneo xgnu NO exogenous of presence in Hsp90, of nitrosylation by and , 1 oee,a motn eeeiu ffc fecs irslto in nitrosylation excess of effect deleterious important an However, . aayi unit catalytic n erae bi eoiinfloighprxcinjury hyperoxic following deposition fibrin decreases and , 191 euto fcrimoyepoenSntoyainb h enzyme the by S-nitrosylation protein cardiomyocyte of Reduction . 178 . n A 60-2770 BAY and α 174 173 uui,aeietfidb uainlaaye snitrosylation as analyses mutational by identified are subunit, 46 . 169 SO-ulmc aeagoa nraei S-nitrosylated in increase global a have mice GSNOR-null . -irslto niisteRo aha,teeydown- thereby pathway, RhoA the inhibits S-nitrosylation . 186,187 o oeiOpeet ppoi nedteilcells endothelial in apoptosis prevents iNO dose Low . 181 8 G otisoe 0cnevdcsens fwhich of cysteines, conserved 30 over contains sGC . G irslto smdltdb h thioredoxin the by modulated is nitrosylation sGC . 184 2 176 idn domain binding n uigtetetwt nitrates with treatment during and 194 yN orle ihnteavoa pc can space alveolar the within corralled CysNO . 192 193 addt ytiersde o nitrosylation for residues cysteine candidate ; hc c shm-ieist etr NO- restore to heme-mimetics as act which , 189 n A 41–2272 BAY and α hsfidn sntuiu oexogenous to unique not is finding This . s 195 125 115 ti osbeta xescysteine excess that possible is It . nedteim NSi abruptly is eNOS endothelium, In . h rnmmrn asg fthat of passage transmembrane the , 180 hnN nonesafree a encounters NO When . β 183 uui rmischaperone its from subunit 186 n shai bronchial asthmatic and htbt nac the enhance both that 168 44 uigbrain During . n inhibiting and 185 inhibiting , 171 92 While . . Posted on Authorea 13 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159466811.11591709 — This a preprint and has not been peer reviewed. Data may be preliminary. onti xd.Eiec o rerdclmechanism. radical exposure micromolar free low a at thiols for of Evidence nitrosation and oxide. Oxidation nitric M. Feelisch to form FL, Jourd’heuil to D, oxide Jourd’heuil nitric 16. with react radicals Thiyl limit. S. diffusion-controlled Goldstein the 2018. G, near Czapski constants P, rate Wardman with LK, S-nitrosothiols Folkes E, protein Madej of 15. site-specificity and formation modification: protein regulation oxide-based Nitric for S-nitrosylation. C. implications Lindermayr I, Kovacs S-nitrosothiols: 14. by formation. donation disulfide NO- of acceleration and and NO, 1995;318(2):279-285. disease. S-nitrosylation NO+, by and functions JS. physiological health Stamler of DR, in Arnelle S-nitrosylation JS. 13. Stamler and TJ, function McMahon protein MW, medicine. Foster of Regulation nitrosylases. 12. 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S-nitrosothiols receptor-specific JT. highly Laitinen and MD, reversible Retamal a KS, in 2005;6(1):21. Monkkonen signaling JR, potential. receptor Savinainen protein-coupled therapeutic T, Kokkola and stimulators discovery NO-independent 187. JP. S- Stasch cyclase: Nitroglycerin-induced HH, guanylate Schmidt A. G, soluble Beuve discovery. Hasko of tolerance. PM, WN, Schmidt activators nitrate P, Duran and Pacher to OV, T, contribute Evgenov Iwahashi cyclase 186. X, guanylyl Fioramonti soluble DD, of 2008;103(6):606-614. desensitization Kim and N, NO nitrosylation the Sayed and oxidation cyclase 185. guanylyl soluble dysfunction: endothelial syndrome. Deconstructing resistance II-induced angiotensin MT. of Gladwin target cyclase, a model. 184. is guanylyl rat cyclase guanylyl soluble hypertensive Soluble a of al. in Desensitization et stress C, A. Huang nitrosative Beuve S, Couloubaly F, PA, Crassous Akker 183. den content. van S-nitrosylation. heme X, by and Ma receptor, activate P, interactions NO 90 Baskaran the subunit protein N, shock its Sayed heat Recep- in 182. and change Oxide oxide rapid Nitric Nitric DJ. driving the Stuehr by Chem. A, Cyclase, cyclase Papapetropoulos Guanylyl guanylate JP, Stasch soluble Soluble A, of Ghosh Modulation 181. Redox S-nitrosylation by Thiol-Based inactivation A. RhoA tor. S. Beuve Li AR, Whorton 180. CA, signaling. Piantadosi channels contractive MS, muscle Na+ Carraway epithelial smooth C, vascular lung regulates Xu inhibits L, virus Lin syncytial Respiratory 179. al. synthase. et nitric-oxide CA, inducible Bosworth up-regulating G, controls by Liu protein-D W, surfactant Song of S-nitrosylation 178. al. et E, Abramova function. EN, inflammatory Atochina-Vasserman treat- CJ, oxide Guo nitric transporter-1. inhibits 177. acid Hyperoxia amino L-type RL. on Auten effects H, via Endou cells 2014;21(13):1823-1836. epithelial MF, alveolar Wempe in BT, effects Tinch ment MV, Brahmajothi is synthase 176. oxide nitric endothelial of S-nitrosylation activity. SM. enzyme Black 2624. decreased PA, and Ross monomerization S, with Levic hippocampal LA, associated rat Brennan in K, injury Ravi brain ischemic 175. in Invovled S-nitrosoglutathione PTEN by of S-nitrosylation S-nitrosylation YJ. region. Song cardiomyocyte CA1 YF, of Sun depression. DS, Reduction Pei myocardial 174. al. sepsis-induced et L, against Zou 2013;304(8):H1134-1146. T, protects Irie PY, reductase protein Sips of value 173. therapeutic The J. Assreuy shock. H, septic Terenzi 2018;1864(1):307-316. MC, experimental Goncalves in ACO, (de)nitrosylation Menegatti injury. attenuates PO, lung oxide Benedet hyperoxic nitric Physiol. 172. neonatal Inhaled Mol in GT. survival Cell Wagenaar prolongs Lung PS, and Hiemstra Physiol deposition BJ, J fibrin Poorthuis and FJ, inflammation Walther pulmonary SA, Horst ter 171. nixdRdxSignal. Redox Antioxid 2014;289(22):15259-15271. 2006;5(9):755-768. erce Res. Neurochem lnInvest. Clin J LSbiology. PLoS 2017;26(3):137-149. 2009;34(8):1507-1512. 2007;293(1):L35-44. 2006;116(9):2330-2332. rcNt cdSiUSA. S U Sci Acad Natl Proc 2008;6(11):e266. mJPyilHatCr Physiol. Circ Heart Physiol J Am iciiae ipyiaat oeua ai fdisease. of basis Molecular acta biophysica et Biochimica ilChem. Biol J 18 ircoie:booyadchemistry. and biology : oxide Nitric 2009;284(11):7294-7306. rcNt cdSiUSA. S U Sci Acad Natl Proc 2007;104(30):12312-12317. mJPyilHatCr Physiol. Circ Heart Physiol J Am 2012;303(5):H597-604. nixdRdxSignal. Redox Antioxid auervesDrug reviews Nature M elbiology. cell BMC 2004;101(8):2619- 2018;74:56-64. icRes. Circ Biol J Am Posted on Authorea 13 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159466811.11591709 — This a preprint and has not been peer reviewed. Data may be preliminary. RNO vasoconstriction and vasodilation (NO (TrxR). hypoxic reductase acceptor Nitrite thioredoxin sources, its by of oxide restored one Nitric then to 3: (Trx) is Figure thioredoxin Thioredoxin of position). transnitrosylation cysteine requires indicating GSO to R-SNO to (X hydrolysis other (GSNOR) NH cysteines GSNHOH any and or reductase of (GSSG) GSH; nitrosoglutathione remake Denitrosylation disulfide to glutathione ] by (GR) produce reductase reduction to glutathione [ GSH by its reduced with NOS. requires reacts nitrosylated which NO the GSNHOH, non-bioavailable intermediate as of such formation R-SNO, to from NO transnitrosation where pathway, by radical or (R-S thiyl radical the thiyl R-SNOH; a form to proteins containing [ NO (GSNO). including species [ (NOx) (R- oxide NO gen S-nitrosothiols produces (NOS) protein synthase oxide of Nitric 3-nitrotyrosine. mechanisms form when to denitrosylation NO tyrosine and of and Nitrogen Transnitrosylation ring SNO) nitrite, aromatic nitrosocysteine. the nitrosocysteine. 2: ion, make form with to Figure to reacts Nitroso peroxynitrite peroxynitrite with thiols reacts reaction, cysteine which residues. competing radical, with thiyl a acidic nitrosylation spontaneously produce In to to and react cysteine sensitive with basic nitrite can Cysteines reacts to superoxide, containing dioxide trioxide. oxidize of cation; dinitrogen motifs” nitroso presence or “SNO become dioxide in to by nitrogen electrons to flanked lose oxidize or are further anion modifications or nitroxyl post-translational nitrate; become and to or oxide, electrons nitric gain can from NO generated species Reactive 1: adenylyl Figure of Study P. Chelikani S, ligands. Legends Dakshinamurti AC Figure novel JL, of Sorensen identification A, and Pritchard a interactions P, in cyclase-GalphaS Dhanaraj activity A, catalytic Jaggupilli cyclase newborn. 195. adenylyl the inhibits of Hypoxia hypertension al. Development pulmonary et Clinical 2018;315(6):L933-L944. persistent KT, and of Santhosh Action model M, of porcine Hinton Mode AS, Riociguat: Sikarwar S-nitrosylation- al. 194. and et activation D, 60-2770 Langleben H-NOX Hypertension. BAY M, Pulmonary nostoc Humbert in into homologous HA, Insights of Ghofrani structures H- 193. al. crystal Nostoc via et to cyclase MG, bound guanylyl complexes. Hahn soluble domain 58-2667) F, of (BAY Martin desensitization cinaciguat V, dependent cyclase. of Kumar guanylyl Structure soluble 192. the al. of et activation for heme-mimetic X, target into Ma alternative 2010;285(29):22651-22657. insights an P, reveals as Baskaran domain cyclase F, NOX guanylate Martin Soluble reductase. al. 191. thioredoxin et K, of asthma. impaired Asosingh in CJ, role to therapy Koziol-White bronchodilator contributes A, S-nitrosylation aorta: Ghosh Augmented mouse 190. RC. hypertensive Webb increasing RC, by II Tostes relaxation angiotensin 2011;29(12):2359-2368. KJ, reduces Allahdadi in inhibition H, relaxation reductase Choi Thioredoxin RC. aorta. 189. mouse Webb in RC, s-nitrosylation Tostes and stress H, oxidative Choi 188. 2 oimntie(NaNO nitrite sodium , B 2 - SOcnb eeae i h rniinmtlptwy hr Orat ihmetal- with reacts NO where pathway, metal transition the via generated be can GSNO ] a eedgnu raiefo irt oossc sehlntie(C nitrite ethyl as such donors nitrite from arise or endogenous be can ) · Biochemistry. ;teN xdto aha hr N where pathway oxidation NO the ); Chest. 2 rntae ti eue oN yxnhn xdrdcae(O) In- (XOR). oxidoreductase xanthine by NO to reduced is it nitrate; or ) 2013;52(20):3601-3608. rcNt cdSiUSA. S U Sci Acad Natl Proc 2017;151(2):468-480. 2 n N and A 2 ,rsligi uontoyaino O.N xdzst nitro- to oxidizes NO NOS. of auto-nitrosylation in resulting ], O 3 htcncnetguahoe(S)t S-nitrosoglutathione to (GSH) glutathione convert can that adoacPharmacol. Cardiovasc J 19 2 O 3 2016;113(17):E2355-2362. ecsdrcl ihatilt omR-SNO; form to thiol a with directly reacts o elBiochem. Cell Mol mJPyilLn elMlPhysiol. Mol Cell Lung Physiol J Am C eirslto fGN leading GSNO of Denitrosylation ] 2 ecswt ho oproduce to thiol a with reacts 2011;58(5):522-527. 2 n moi.[ ammonia. and H 2018;446:63-72. 2 H 5 NO ilChem. Biol J Hypertens. J 2 2 rother or ) H later OH, D Posted on Authorea 13 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159466811.11591709 — This a preprint and has not been peer reviewed. Data may be preliminary. yls sC steitaellrrcpo fN,gnrtn ylcGPipratfratra relaxation, sGC, arterial of nitrosylation for include important formation Glu- GMP SNO guanylate cyclic of effects circulation. Soluble generating vasodilation. Vasoconstrictor NO, distal inhibiting proteins. circuit. of the pulmonary other receptor the transnitrosylate to in intracellular to particularly NO the locally delivering is SNO (sGC) (nitrosohemoglobin), deliver nitrosylation cyclase include can SNO-Hb formation nitrosylation form SNO directly (GSH) (O of to proteins tathione effects (SNO) superoxide (Hb) Vasodilator nitrosothiols with hemoglobin (ONOO-). generates combination peroxynitrite of NO form rapid NO. to by of superoxide conversion, source with exogenous and an oxidation is through (iNO) oxide nitric haled 20 2 – ,o hog Oreaction NO through or ), Posted on Authorea 13 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159466811.11591709 — This a preprint and has not been peer reviewed. Data may be preliminary. 21