Gasotransmitters in health and disease: a mitochondria-centered view

University of Groningen

Gasotransmitters in health and disease

Hendriks, Koen Dw; Maassen, Hanno; van Dijk, Peter R; Henning, Robert H; van Goor, Harry;

Hillebrands, Jan-Luuk

Published in:

Current Opinion in Pharmacology

DOI:

10.1016/j.coph.2019.07.001

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Hendriks, K. D., Maassen, H., van Dijk, P. R., Henning, R. H., van Goor, H., & Hillebrands, J-L. (2019). Gasotransmitters in health and disease: a mitochondria-centered view. Current Opinion in Pharmacology, 45, 87-93. https://doi.org/10.1016/j.coph.2019.07.001

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Gasotransmitters

in

health

and

disease:

a

mitochondria-centered

view

Koen

DW

Hendriks

,

Hanno

Maassen

,

Peter

R

van

Dijk

,

Robert

H

Henning

,

Harry

van

Goor

and

Jan-Luuk

Hillebrands

Gasotransmittersfulfillimportantrolesincellularhomeostasis

havingbeenlinkedtovariouspathologies,including

inflammationandcardiovasculardiseases.Inadditiontothe

knownpathwaysmediatingtheactionsofgasotransmitters,

theireffectsinregulatingmitochondrialfunctionareemerging.

Giventhatmitochondriaarekeyorganellesinenergy

production,formationofreactiveoxygenspeciesand

apoptosis,theyareimportantmediatorsinpreservinghealth

anddisease.Preservingorrestoringmitochondrialfunctionby

gasotransmittersmaybebeneficial,andmitigatepathogenetic

processes.Inthisreviewwediscusstheactionsof

gasotransmitterswithfocusontheirroleinmitochondrial

functionandtheirtherapeuticpotential.

Addresses

1_{DepartmentofClinicalPharmacyandPharmacology,University}

MedicalCenterGroningen,UniversityofGroningen,Groningen,The Netherlands

2_{DepartmentofSurgery,UniversityMedicalCenterGroningen,}

UniversityofGroningen,Groningen,TheNetherlands

3_{DepartmentofInternalMedicine,UniversityofGroningen,University}

MedicalCenter,Groningen,TheNetherlands

4

DepartmentofPathologyandMedicalBiology,PathologySection, UniversityofGroningen,UniversityMedicalCenterGroningen, Groningen,TheNetherlands

Correspondingauthor:Hillebrands,Jan-Luuk(j.l.hillebrands@umcg.nl)

5

Theseauthorscontributedequally.

6_{Theseauthorssharedseniorauthorship.}

CurrentOpinioninPharmacology2019,45:87–93

ThisreviewcomesfromathemedissueonCardiovascularandrenal EditedbyFrancesPlane

https://doi.org/10.1016/j.coph.2019.07.001

1471-4892/_ã2019TheAuthors.PublishedbyElsevierLtd.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creative-commons.org/licenses/by-nc-nd/4.0/).

Introduction

Gasotransmitters are small, chemically reactive, mole-cules with short half-lives that played crucial roles in the development of life.Nitric oxide(NO) and carbon monoxide(CO)werethefirstdescribedandbest-known gasotransmitters,withhydrogensulfide(H2S)being

dis-covered more recently. Given that gasotransmitters

diffusefreelyacrosscellularmembranes,theycan poten-tially regulateabroadrange of important cellular func-tions throughout the body. These include regulating vascular tone [1], neuromodulation [2], paracrine cell signaling [3], and mitochondrial function [4]. Because oftheireffectonkeycellularfunctions,anydisturbance in theiravailabilityis linkedto avarietyof pathological conditions. The mitochondrion isan organelle targeted bygasotransmitters wheretheymodulatemitochondrial function, including adenosine triphosphate (ATP) pro-duction, reactive oxygen species (ROS) formation and initiation of apoptotic cascades,which are allimportant mediators ininflammationanddisease.

Thepresentreviewprovidesanoverviewofrecentfindings ontheroleofgasotransmittersmodulatinginflammation, diseasepathogenesis,andmitochondrialfunction.Italso exploresavenuestotargetenzymeactivityorsupply gaso-transmitterdonorsastherapeuticinterventions.

Gasotransmitter

synthesis

and

bioavailability

Several enzymes can produce gasotransmitters. NO is formed by the conversion of L-arginine to L-citrulline,

anoxidativeprocessregulatedbythreesubtypesofnitric oxidesynthases(NOS)withdifferentexpressionlevelsin differentcells:neuronal(nNOS),endothelial(eNOS)and inducible (iNOS) nitric oxide synthase. Within a cell, iNOSandnNOSare mainlycytosolic,althoughnuclear localizationofnNOSin ratastrocyteshasbeen reported [5].eNOSismembrane-bound,tofacilitatereleaseofNO to theextracellular environment.

CO is synthesized by conversion of heme to biliverdin throughhemeoxygenase(HO),anenzymethatoccursin three differentisoforms:HO-1, HO-2 andHO-3.HO is mainly located in the endoplasmic reticulum (ER), but similartoNOS,HOisalsopresentinthemitochondria[6]. H2Sisderivedfromcysteinebyenzymaticreactions

cata-lyzedbymainlycytosoliccystathionineb-synthase(CBS), cystathionineg-lyase(CSE)andcysteineaminotransferase (CAT).However,inlinewiththemitochondrialNOand CO, CBS and CSE translocate to mitochondria during cellular stress such as hypoxia [7]. Additionally, H2S is

produceddirectlywithinmitochondriaby 3-mercaptopyr-uvate sulfur-transferase (3MST) [8]. Summarizing, the production of gasotransmitters is regulated by different

enzymes, of which spatial expression patterns differ between organs and cell types. All gasotransmitters can beproducednearorinsidemitochondria,whichindicatesa potentiallyimportantroleofthesemoleculesin mitochon-drialfunction.

Asimplifiedoverviewofthesynthesisandbioavailability ofgasotransmittersisoutlinedin Figure1.

Gasotransmitters

in

physiology

and

disease

Aplethoraofphysiologicaleffectsofgasotransmittershave beendocumented.Forinstance,gasotransmitters,bothvia directintracellulareffectsandreleasedintheextracellular space,playanimportantroleinregulationofvasculartone, reduceoxidativestress,andinduceangiogenesis[9].More specifically,COisinvolvedinregulationofendothelialcell survivalandproliferation,protectionfrom ischemia-reper-fusion injury (IRI), vasorelaxation and inhibition of pro-inflammatory responses. HO-1 acts as an inflammation-neutralizing factor regulated by nuclear-factor-E2-related factor-2 (Nrf2), as observed in lung inflammation after intestinal IRI[10]. NO regulatesnumerous intra-cellular and inter-cellular processes such as platelet aggregation, endothelialadhesionofleukocytesandrelaxationofsmooth musclecells.Moreover,iNOSactivatedby nuclear-factor-kappaB(NF-kB)activationand signal-transducer-and-acti-vator-of-transcription-1a(STAT-1a)results inelevatedNO levelsandrepresentsanimportantcomponentinthe inflam-matoryresponse[11].ExcessproductionofNO,leadingto

nitrosative stress, is correlated with the severity of liver disease in mice [12]. In contrast, the anti-inflammatory actionof NOisrevealedin iNOS-knockouthigh-fat-diet fedmice thatshowanincreasedinflammationleading to liver fibrosis [13]. These data indicate that NO harbors potentialtoexertbothpro-inflammatoryand anti-inflamma-toryfunctions,mostlikelyinadose-dependentmanner.H2S

hasimportantanti-inflammatoryandantioxidantpotential, andcausesrelaxationof blood vessels[14]. H2S protects

endothelial cells from lipopolysaccharide (LPS)-induced inflammationby blocking NF-kB transactivation [15].In addition,exogenousH2Streatmentdecreasedinflammation

and IRI following intestinal ischemia, whereas eNOS knockout mice were not protected by exogenous H2S.

Thesedata suggest that H2S shows protective effects in

aneNOS-dependentmanner[16].NADPHoxidase(Nox), amitochondrialsourceofROS,isakey-signalingpathway responsible for the increased inflammatory response of macrophagesin vitro andin septic mice [17,18], which couldbeamelioratedbyendogenousH2S.

Reduced bioavailability of gasotransmitters has been observed in vascular pathology [19], aging [20] and aging-related pathologies [21],renalpathology [22] and diabetes [23] (Figure 2). These associations suggest causality between gasotransmitter bioavailability and diseasepathogenesis.

The various pathways, in which gasotransmitters are involved in disease pathogenesis and inflammation becomeofevenmoreinterestwhenlookingat mitochon-drial dysfunction, for example, in sepsis. Brealey et al. demonstrated lowered ATP levels, overproduction of NO, and mitochondrial dysfunction in skeletal muscle biopsies of septic patients [24]. Using H2S and CO,

potentiation of mitochondrial function could preserve tissuefunctionduringsepsis[25].Theauthorssuggested varioustherapeutic interventions to increase exogenous and endogenous H2S production, to specifically inhibit

iNOSandto stimulateHO-1activity, inorder totarget mitochondrialpathwaysinsepsis andinflammation. Aschematicoverviewofsomeoftheinvolvedpathwaysis shownin Figure2.

Mitochondrial

aspects

of

gasotransmitters

Mitochondria,‘thepowerhousesofthecell’representthe mainsourceof energyusing oxidative phosphorylation, but also modulate important regulatory and signaling processes. In oxidative phosphorylation, mitochondria oxidize substrates via the electron transport chain (ETC)tocreateaprotongradient,whichisusedtodrive the ATP synthesis. Gasotransmitters regulate this pro-cess,supportingnormalphysiology.

NO, CO, and H2S all reduce the ETC activity via

inhibitionofcytochromecoxidase(COX)inareversible,

88 Cardiovascularandrenal

Figure1 CSE HO NOS CBS 3MST H2S l-arganine l-citrulline heme biliverdin CO NO CAT

Current Opinion in Pharmacology

Ageneraloverviewofthecellularsynthesisandbioavailabilityof gasotransmitterswithinacell.

3MST(3-mercaptopyruvatesulfur-transferase),CBS(cystathionine b-synthase),CSE,(cystathionineg-lyase)andCAT(cysteine aminotransferase)produceH2S(hydrogensulfide).HO(heme

oxygenase)producesCO(carbonmonoxide).NO(Nitricoxide)is producedbyNOS(nitricoxidesynthase).

fast-actinganddose-dependentmanner[1].Accordingly, gasotransmitters may preserve normal ETC function. Indeed, administration of NO and CO protected mito-chondria, presumably by decreasing ROS production, during hemorrhagicshock [26].Furthermore, upregula-tion of HO-1 normalized mitochondrial function and decreasedROSformationinIRI[27].AlsoH2Sprotects

theETCthroughdifferentmechanisms[28].Inlinewith this,CSEknockoutmicearemoresusceptibletocerebral IRIcomparedtocontrols;whichcouldbereversedusing exogenousH2S[29].Interestingly,incontrasttoNOand

CO, H2S can act as hydrogen donor and functions as

substrate formitochondrialrespiration [30].

High-dose treatment with CO, NO or H2S can almost

completelyinhibitmitochondrialactivity, andespecially H2Sharborsthepotentialtosuppressmetabolisminasafe

manner:theinductionofahypometabolicstate[31,32]. This hibernation-like state has is protective to IRI, thereby having therapeutic potential in, for example, organtransplantation[33].

Besides direct effects on mitochondrial function, gasotransmittersplayanimportantroleinROS scaveng-ing. NO is a potent antioxidant by virtue of its fast reaction with hydroxyl radicals, superoxides and lipid peroxides[34].ExogenousH2Sadministrationprotected

cardiactissuefrom ROSdamagein amyocardialinjury ratmodel [35].

Inadditiontothedirectscavengingpotential, gasotrans-mittersarealsoimportantintheactivationofscavenging pathways, such as Nrf2 and glutathione (GSH). Kelch-like-ECH-associated-protein-1(Keap1)servesasa nega-tive regulatorof Nrf2, during stress-freephysiology, by binding toNrf2 in thecytoplasmand promoting degra-dationofNrf2.CellularstressprovokedbyROS, inacti-vatesKeap1andthereforestabilizesNrf2,allowing trans-location to the nucleus and activation of its target: the antioxidant-response-element (ARE) [36,37]. H2S can

promote Keap1-dependent Nrf2 stabilization, which facilitates Nrf2 translocation into the nucleus [38]. Indeed, exogenous NaHS administration to a diabetic

Figure2

H

S

Disease

- Smooth muscle cell relaxation - IRI protective - Adhesion leukocytes to endothelium - Platelet aggregation - Anti-inflammatory

- Smooth muscle cell relaxation

- Regulation endothelial cells

NO

CO

Current Opinion in Pharmacology

Aschematicoverviewofsomeofthedisease-relatedpathwaysgasotransmittersareinvolvedin.

Allthreegasotransmitters,H2S(hydrogensulfide),CO(carbonmonoxide)andNO(nitricoxide)showedmitigatingeffectsinavarietyofdiseases.

stressed rat model resulted in increased nuclear Nrf2 levels, activation of superoxide dismutase (SOD) and limited the numbers of apoptotic cells [39]. Besides increasingGSHproduction,H2Sisthoughtto

redistrib-ute GSH into the mitochondria to directly scavenge mitochondrial-produced superoxides [40]. CO exposure in transplanted rat lungs protected against apoptosis, likely via increased SOD activity and decreased ROS-induceddamage[41].

Another important pathway that gasotransmitters are involvedin is theopening of themitochondrial perme-ability transition pore (mPTP). Full opening of these pores in responseto several factors includingexcessive ROSproductionandcalcium-overload,resultsinalossof mitochondrialmembranepotentialandreducedoxidative phosphorylation, mitochondrial swelling and a burst of ROS, eventually leading to necrosis or apoptosis [42]. ExogenousH2SinhibitsapoptosisviablockadeofmPTP

formationandcytochromec(cytc)release[43].Apoptosis can be activated by the Bcl2-family, cyt c release andcaspase activation. BothNO and CO areknown to suppresstheBcl2-familyand caspaseactivation[44,45]. These findings indicate that gasotransmitters have an importantroleinthecellularenergeticstateandapoptosis by regulating several mitochondrial-related and ROS-relatedactions,asoutlinedin Figure3.

Treatment

perspectives

Exogenous administration of gasotransmitters is an emergingtherapeutic option.Theoldestand mostused donoristheacuteNOdonornitroglycerin,causing vaso-dilationandrelievingacutepainduringanginapectoris. Another clinically relevant NO donor in current use is sodium nitroprusside (SNP), also playing an important role in vasorelaxation. On the basis of these successes, severalNOdonorsweresynthesized,amongwhich com-bined therapeutics,such as NO-NSAID[46]. Addition-ally,downstreamNO-modulating drugsweretested,for example, the phosphodiesterase 5 (PDE5) inhibitor sildenafil [47].Sildenafiltreatment increasedactivity of the NO/cGMP pathway and protected from oxidative damageandapoptosisindiabetes[48]andcardiovascular dysfunction[49].Incontrast,recentfindingsinpregnant womenwithfetalgrowthrestrictionrevealeddetrimental effects of sildenafil treatment [50]. In line with the functions of CO, carbon monoxide-releasing-molecules (CORMs) have anti-apoptotic, anti-inflammatory, and antioxidanteffects [51]. The fast releasing H2S donors

NaHS and Na2S are widely used in the experimental

settingandinduceahypometabolicstate[32].However, these donors are not suitable for precise and sustained administration. A potential alternative can be found in thiosulfate(STS).STSshowedpositiveeffectson hyper-tension and renalinjury [52].The potential of STS on reducingcardiacischemiaisnowbeingclinicallytested.

90 Cardiovascularandrenal

Figure3 ETC Apoptosis cascade CO Antioxidant capacity ATP GSH H2S + CO CO + functional dysfunctional +

Disease

-Current Opinion in Pharmacology

Asimplifiedoverviewoftheinteractionsbetweengasotransmittersandmitochondria.

Recently, toexploit the protective properties of H2S,

slow-releasing H2S molecules havebeen synthesized,

includingmorpholin-4-ium4methoxyphenyl (morpho-lino) phosphinodithioate (GYY4137), 10-oxo-10-[4- (3-thioxo-3H-1,2-dithiol-5-yl)phenoxy]decyl]triphenyl-phosphonium (AP39),andanatural garlic-derived poly-sulfidecompound–diallyltrisulfide(DATS)conjugatedto amesoporoussilicananoparticles(MSN)carrier(DATS– MSN) (Table 1). Whereas GYY4137 is not specifically targeted,AP39isamitochondria-targetedH2Sdonor,with

potentprotectiveeffectsinanorgantransplantationmodel [54].DATS–MSNshowssuperioranti-apoptotic, anti-oxidant and anti-inflammatory abilities as compared to NaHS [53]. Also ROS-triggered H2S donors [55] and

slow-releasing NO/H2S hybrid molecules have been

developed(e.g.ZYZ-803)[56](Table1),theiruseshowing promisingprotectiveeffectsagainstheartfailure[57].

Conclusion

Gasotransmitters playa keyrole in the pathogenesisof various diseases, with a unifying role in preservation of mitochondrialfunction.H2S,CO,andNOcontribute

to maintainingnormalmitochondrial functionandshow abroadvarietyofpotentialtherapeuticproperties: influ-encing ETC activity,directscavenging of ROS, activa-tionofscavengingpathways,andattenuationofapoptosis. Accordingly, gasotransmitters are potential efficacious drugs and this insight has led to the synthesis of long-lasting and slow-releasing donors. Although promising results have been obtained in experimental disease

models, these compounds have not been extensively testedintheclinic.Thisurgestheneedformore exten-siveresearch and newcompounds.Amitochondrial tar-getedcombinationofH2S–NO–COdonorisanattractive

concept to protect mitochondria from noxious insults; whether this concept is actually feasible remains to be seenin thenear future.

Conflict

of

interest

statement

Nothingdeclared.

Acknowledgements

KDWHandHMaresupportedbytheMD-PhDprogramoftheGraduate SchoolofMedicalSciences,UniversityMedicalCenterGroningen.The authorsthankMaaikevanderMeulenfordesigningthefigures.

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Table1

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