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Calcium signaling and the novel anti-proliferative effect of the UTP-sensitive P2Y11 receptor in rat cardiac myofibroblasts

2015Journal article Open access
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dc.contributor.authorCertal, Mariana
dc.contributor.authorVinhas, Adriana
dc.contributor.authorPinheiro, Ana Rita
dc.contributor.authorFerreirinha, Fátima
dc.contributor.authorBarros-Barbosa, Aurora Raquel
dc.contributor.authorSilva, Isabel
dc.contributor.authorCosta, Maria Adelina
dc.contributor.authorCorreia-de-Sá, Paulo
dc.date.accessioned2016-01-27T16:52:19Z
dc.date.available2016-01-27T16:52:19Z
dc.date.issued2015
dc.description.abstractDuring myocardial ischemia and reperfusion both purines and pyrimidines are released into the extracellular milieu, thus creating a signaling wave that propagates to neighboring cells via membrane-bound P2 purinoceptors activation. Cardiac fibroblasts (CF) are important players in heart remodeling, electrophysiological changes and hemodynamic alterations following myocardial infarction. Here, we investigated the role UTP on calcium signaling and proliferation of CF cultured from ventricles of adult rats. Co-expression of discoidin domain receptor 2 and -smooth muscle actin indicate that cultured CF are activated myofibroblasts. Intracellular calcium ([Ca2+]i) signals were monitored in cells loaded with Fluo-4 NW. CF proliferation was evaluated by the MTT assay. UTP and the selective P2Y4 agonist, MRS4062, caused a fast desensitizing [Ca2+]i rise originated from thapsigargin-sensitive internal stores, which partially declined to a plateau providing the existence of Ca2+ in the extracellular fluid. The biphasic [Ca2+]i response to UTP was attenuated respectively by P2Y4 blockers, like reactive blue-2 and suramin, and by the P2Y11 antagonist, NF340. UTP and the P2Y2 receptor agonist MRS2768 increased, whereas the selective P2Y11 agonist NF546 decreased, CF growth; MRS4062 was ineffective. Blockage of the P2Y11receptor or its coupling to adenylate cyclase boosted UTP-induced CF proliferation. Confocal microscopy and Western blot analysis confirmed the presence of P2Y2, P2Y4 and P2Y11 receptors. Data indicate that besides P2Y4 and P2Y2 receptors which are responsible for UTP-induced [Ca2+]i transients and growth of CF, respectively, synchronous activation of the previously unrecognized P2Y11 receptor may represent an important target for anti-fibrotic intervention in cardiac remodeling.pt_PT
dc.identifier.doi10.1016/j.ceca.2015.08.004pt_PT
dc.identifier.issn0143-4160
dc.identifier.urihttp://hdl.handle.net/10400.22/7543
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relation2014 - Strategic Project
dc.relationPURINERGIC MECHANISMS INVOLVED IN THE CROSSTALK BETWEEN FIBROBLASTS AND CARDIOMYOCYTES AS PUTATIVE PHARMACOLOGICAL TARGETS FOR THE MANAGEMENT OF CARDIAC REMODELLING
dc.relationPURINERGIC MODULATION OF NEUROTRANSMITTER TRANSPORTERS IN HUMAN MESO-TEMPORAL LOBE EPILEPSY MTLE
dc.relationTARGETING THE PURINOME TO CONTROL HYPERACTIVITY OF THE HUMAN URINARY BLADDER
dc.subjectCardiac fibroblastspt_PT
dc.subjectMyofibroblastpt_PT
dc.subjectUTPpt_PT
dc.subjectP2Y2 receptorpt_PT
dc.subjectP2Y4 receptorpt_PT
dc.subjectP2Y11 receptorpt_PT
dc.subjectIntracellular calciumpt_PT
dc.subjectFibroblast cell growthpt_PT
dc.subjectATP releasept_PT
dc.subjectCX43-containing hemichannelspt_PT
dc.subjectAdenylate cyclasept_PT
dc.subjectCyclic AMPpt_PT
dc.subjectEPACpt_PT
dc.titleCalcium signaling and the novel anti-proliferative effect of the UTP-sensitive P2Y11 receptor in rat cardiac myofibroblastspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitle2014 - Strategic Project
oaire.awardTitlePURINERGIC MECHANISMS INVOLVED IN THE CROSSTALK BETWEEN FIBROBLASTS AND CARDIOMYOCYTES AS PUTATIVE PHARMACOLOGICAL TARGETS FOR THE MANAGEMENT OF CARDIAC REMODELLING
oaire.awardTitlePURINERGIC MODULATION OF NEUROTRANSMITTER TRANSPORTERS IN HUMAN MESO-TEMPORAL LOBE EPILEPSY MTLE
oaire.awardTitleTARGETING THE PURINOME TO CONTROL HYPERACTIVITY OF THE HUMAN URINARY BLADDER
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/PTDC%2FDTP-FTO%2F0802%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/PEst-OE%2FSAU%2FUI0215%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F81414%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/FARH/SFRH%2FBD%2F79259%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/FARH/SFRH%2FBD%2F88855%2F2012/PT
oaire.citation.endPage533pt_PT
oaire.citation.issue5pt_PT
oaire.citation.startPage518pt_PT
oaire.citation.titleCell calciumpt_PT
oaire.citation.volume58pt_PT
oaire.fundingStream5876-PPCDTI
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamFARH
oaire.fundingStreamFARH
person.familyNamePinheiro
person.givenNameAna Rita
person.identifier.orcid0000-0003-4310-7652
person.identifier.ridB-4018-2017
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationa99bce31-2fe7-4e36-af87-32d684d22ce0
relation.isAuthorOfPublication.latestForDiscoverya99bce31-2fe7-4e36-af87-32d684d22ce0
relation.isProjectOfPublicationa14569bd-07b1-4b13-b6e1-a04d2a2005e3
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