RAAS系統研究的新熱點

(TheUpdateOfRAASResearch)

重慶醫科大學附屬第一醫院心內科陳明2021-4，廣州1ThehotresearchofRAASIntracellularangiotensinIIAngIIreceptors,newagonistandantagonistACE2andACE2activatorReninandrenininhibitorRAASandcardiacarrhythmiaBrainangiotensinII2ClassicalcirculatingRAAS3NewexpandedviewofRAAS4RAAS:fromcirculationtotissue,thenintrcellularintracellularangiotensinIIACEisamultifunctionalenzymeequallyimportantinthemetabolismofvasodilatorandantifibroticpeptides.Asthemembrane-boundform,ACEfunctionsasa“receptor〞thatinitiatesintracellularsignalingleadingtogeneexpression.receptor-dependentandindependent5AngIIreceptors6AngIIReceptors:AT1AT1:

?decreaseofplasmaadiponectin;

?pro-inflammatorymodulation;

?increasedinsulinsecretion;

?β-cellapoptosis;

?reductionofgluconeogenesis?increasedplasmatriglycerides;7AT2:Newtargetsofneuronaldisease?ThecellulartargetsoftheAT2receptorinneuronaltissuearenotyetclearlyidentifiedThefindingsontheneurotrophicactionsofAT2receptorstimulationmayprovideabasisforthedesignofnewtherapeuticconceptsfortreatmentofhumanperipheralnerveinjuries,diabeticneuropathy,neurodegenerativedisordersandstroke

8AT2agonistandantagonistAT2receptoragonist:CGP42112AT2receptorantagonist:AkishitaetaldemonstratethattheAT2receptorantagonistPD123319increasedneointimaformationinthecuff-inducedvascularinjurymodelinmice9NewpossibleARBsThemostsuccessfulapproachhasbeentomodifyAT1-selectivecompoundstoenhancetheirAT2affinity.Anacylsulfonamidegroup,isanisostericreplacementforthetetrazolering,toprovideAT2affinity.Newcompoundsknownas“balanced〞AT1/AT2receptorantagonists(L-162132)-equalaffinityfortheAT1andAT2

10AngIIreceptors11AT4:animportanttargetfordrugdevelopment

Insulin-regulatedaminopeptidasereceptors,IRAP.AwiderangeofstudieshavemadeitclearthatIRAPmightbecomeanimportanttargetfordrugdevelopmentagainstdifferentpathologiessuchasAlzheimer'sdisease,epilepsyandischemia.-HeartFailRev.2021Sep;13(3):321-3712ACE2-Ang-(1–7)-Masaxis13ACE2-Ang-(1–7)-MasaxisAngiotensin-convertingenzyme2andAng1–7mayplayanimportantroleincardiovascularphysiologyandpathophysiology,e.g.bymodulatingorcounterbalancingexcessactivityofthe‘classical’RAS.

-CircRes2006;98:463–7-ProgBiophysMolBiol2006;91:163–9814InvolvementofACE2inlunginjuryACE2hasbeenshowntofunctionasareceptorofsevereacuterespiratorysyndrome(SARS)coronavirus-NatMed2005;11:875–9-JMolMed2006;84:814–20ACE2mayprotectagainstthepotentiallylethallunginjuryassociatedwithSARS

-Nature2005;436:112–615新成員,新靶點,新發現:ACE2Activator

Structure-BasedIdentificationofSmall-MoleculeAngiotensin-ConvertingEnzyme2ActivatorsasNovelAntihypertensiveAgents

2021;51;1312-1317;originallypublishedonlineApr7,2021;Gubala,DavidA.OstrovandMohanK.RaizadaJoséA.HernándezPrada,AndersonJ.Ferreira,MichaelJ.Katovich,VinayakShenoy,16ACE2ActivatorInthisstudyisthatXNT,acompoundthatenhancesACE2activity,causesconsiderablereductionsinBPandastrikingreversalofcardiacandrenalfibrosisintheSHRmodelofhypertension.Hereforthefirsttimeastructure-baseddrug-discoveryapproachtoenablerationaldevelopmentofenzymeactivators.-Hypertension2021;51;1312-131717Ang-〔1-7)andMasagonistThenonpeptideangiotensin-(1–7)receptorMasagonistAVE-0991Masantagonist:A-779andD-Pro7-Ang-(1–7).Angiotensin(1-7)preventheartdysfunctionandleftventricularremodelingcausedbyrenaldysfunctionin5/6nephrectomymice.----HypertensResadvanceonlinepublication,27March2021;18Chymase

:RecognitionofAlternativepathwaysofAngIIgeneration

ChymaseisenzymaticallyinactiveinnormalvasculartissueandmayproduceAngIIonlyindamagedoratheroscleroticarterialwalls.ChymaseinhibitorsHumanHeartChymase:

playanimportatnroleinLVH

19ReninandrenininhibitorsGreatexpectationsarenowgeneratedbytheintroductionofrenininhibitors.Therecentintroductionofthefirstorallyeffectiverenininhibitor,aliskiren,hasraisedadditionalinterestinnewpossibilitiesofalmostcompleteblockadeofRASasatool20Reninandrenin

inhibitors:DRIsEarlyreportsontheuseofaliskirenarepromising,showingatleast,anantihypertensiveeffectofaliskirenpotentasthoseofotherantihypertensivedrugs.Inparticular,thecombinationofrenininhibitorswithACEinhibitorsandARBsmayofferasolutiontothe‘reninescape’phenomenon.21AntihypertensiveEffectsofAliskirenComparedWithPlacebo22Reninandreninreceptor:independentofAII

23ReninandReninreceptor24RAASandcardiacarrhythmiaTherenin-angiotensin-aldosteronesystem(RAAS)hasemergedasanimportanthormonalsystemintheinitiationandpathogenesisofatrialfibrillation(AF).Therefore,angiotensin-convertingenzymeinhibitors(ACEIs)orangiotensinreceptorblockers(ARBs)areemergingasnoveldrugsforthepreventionofAF.25AngIIandVesselInjureAngIIappearstoplayacentralroleinmanystimulithatgovernarterialageinganditsfunctionalresponses.Therapeuticapproachestoreducetheneointimalformationcausedbyballooninjuryhavebeenfocusedmainlyonexperimentalmodelsofrestenosis.

26ARBandBalloonInjureHyperRes2007;10:971-97827RAASandMetabolismofGlucoseandLipidsAngIIandinsulinresistanceRAASinhibitorsandDMRAASandPPARγDirectReninInhibitionImprovesSystemicInsulinResistance

28Newstudy:NAVIGATORPreliminaryevidencethatRAASinhibitorsreduceincidentdiabetesisintriguing.WhetherARBscanreduceincidentdiabetesandrelatedcardiovascularoutcomesisawaitedwiththeNateglinideandValsartaninImpairedGlucoseToleranceOutcomesResearch(NAVIGATOR)trial.29RAASandAdiposetissue,obesityAdiposetissuecontainsallcomponentsofRASandmaybeinvolvedintheregulationofvisceraladiposetissueaccumulation.Thus,visceralRASmayplayaroleinthepathophysiologyofthemetabolicsyndrome.AdiposetissuewasshowntobeanimportantsourceofbothlocalandcirculatingAGT30RAASandAdiposetissue,obesityTheadiposeRAShasabilitytostimulatebothpreadipocytedifferentiationandlipogenesisinmatureadipocytes.AngiotensinIIenhanceslipogenesisbydirectlyincreasingtheactivityandexpressionofkeylipogenicenzymes,leadingtoincreasedtriglyceridesynthesisandstorageandultimately“fatter〞fatcells.31

AldosteroneandMyocardial/RenalFibrosisExperimentalevidenceindicatesthataldosterone,besidesitsmineralcorticoidproperties,directlycontributestoacceleratemyocardialandrenaldamagethroughpromotionofcellgrowth,fibrosisandinflammation.Newreceptorblocker:EplerenoneTheCombinationwithACEIand/orARB32RAASandrenaldiseasesIntensifiedinhibitionofrenin-angiotensinsystem:awaytoimproverenalprotection?Effectsofrenin-angiotensinsysteminhibitionend-organprotection:Canwedobetter?33AfterOntarget:

Howabou

dualblockade

ofRAAS?Renalinterstitialfluidhasbeenshowntocontain

roughly1000-foldhigherconcentrationsofAngIIand

AngIIIthanfoundintheplasma

-JClinInvest1990;86:1352–7.34OngoingstudyaboutdualblockadeTheLong-TermImpactofRASInhibitiononCardiorenalOutcomes(LIRICO)studyComparethecardiorenoprotectiveeffectsofACEinhibitorsandARBsinpatientswithalbuminuria,andclarifytheroleofdualblockade.TheVANEPHRON-DstudymayeventuallyprovidemoredefinitivedataontheeffectofthecombinationofanACE-IandanARBontheprogressionofkidneydisease.35OngoingstudyaboutdualblockadeTheVANEPHRON-DstudymayeventuallyprovidemoredefinitivedataontheeffectofthecombinationofanACE-IandanARB(losartanmonotherapyorlosartan/lisinoprilcombinationtherapy)ontheprogressionofkidneydisease.36BrainangiotensinII:newdevelopments,unansweredquestionsandtherapeuticopportunities.TherearetwoAngiotensinIIsystemsinthebrain.

37BrainangiotensinIIManyquestionsremain.HowisbrainAngiotensinIIformed,metabolized,anddistributed?WhatistheroleofbrainAT2receptors?WhatarethemolecularmechanismsinvolvedinthecerebrovascularremodelingandinflammationwhicharepromotedbyAT1receptorstimulation?HowdoesAngiotensinIIregulatethestressresponseathigherbraincenters?

38IstheelevationofcirculatingAngIIgoodforpreventionofStroke?Inprimaryorsecondaryst