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Novel Cardiokine GDF3 Predicts Adverse Fibrotic Remodeling After Myocardial Infarction

dc.rights.licenseopenen_US
dc.contributor.authorMASURKAR, Nihar
dc.contributor.authorBOUVET, Marion
dc.contributor.authorLOGEART, Damien
dc.contributor.authorJOUVE, Charlene
dc.contributor.authorDRAME, Fatou
dc.contributor.authorCLAUDE, Olivier
dc.contributor.authorROUX, Maguelonne
dc.contributor.authorDELACROIX, Clement
dc.contributor.authorBERGEROT, Damien
dc.contributor.authorMERCADIER, Jean-Jacques
dc.contributor.authorSIROL, Marc
dc.contributor.authorGELLEN, Barnabas
dc.contributor.authorLIVROZET, Marine
dc.contributor.authorFAYOL, Antoine
dc.contributor.authorROBIDEL, Estelle
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorTREGOUET, David-Alexandre
dc.contributor.authorMARAZZI, Giovanna
dc.contributor.authorSASSOON, David
dc.contributor.authorVALENTE, Mariana
dc.contributor.authorHULOT, Jean-Sebastien
dc.date.accessioned2023-02-17T09:15:28Z
dc.date.available2023-02-17T09:15:28Z
dc.date.issued2023-02-07
dc.identifier.issn1524-4539 (Electronic) 0009-7322 (Linking)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/171980
dc.description.abstractEnBACKGROUND: Myocardial infarction (MI) induces a repair response that ultimately generates a stable fibrotic scar. Although the scar prevents cardiac rupture, an excessive profibrotic response impairs optimal recovery by promoting the development of noncontractile fibrotic areas. The mechanisms that lead to cardiac fibrosis are diverse and incompletely characterized. We explored whether the expansion of cardiac fibroblasts after MI can be regulated through a paracrine action of cardiac stromal cells. METHODS: We performed a bioinformatic secretome analysis of cardiac stromal PW1(+) cells isolated from normal and post-MI mouse hearts to identify novel secreted proteins. Functional assays were used to screen secreted proteins that promote fibroblast proliferation. The expressions of candidates were subsequently analyzed in mouse and human hearts and plasmas. The relationship between levels of circulating protein candidates and adverse post-MI cardiac remodeling was examined in a cohort of 80 patients with a first ST-segment-elevation MI and serial cardiac magnetic resonance imaging evaluations. RESULTS: Cardiac stromal PW1(+) cells undergo a change in paracrine behavior after MI, and the conditioned media from these cells induced a significant increase in the proliferation of fibroblasts. We identified a total of 12 candidates as secreted proteins overexpressed by cardiac PW1(+) cells after MI. Among these factors, GDF3 (growth differentiation factor 3), a member of the TGF-β (transforming growth factor-β) family, was markedly upregulated in the ischemic hearts. Conditioned media specifically enriched with GDF3 induced fibroblast proliferation at a high level by stimulation of activin-receptor-like kinases. In line with the secretory nature of this protein, we next found that GDF3 can be detected in mice and human plasma samples, with a significant increase in the days after MI. In humans, higher GDF3 circulating levels (measured in the plasma at day 4 after MI) were significantly associated with an increased risk of adverse remodeling 6 months after MI (adjusted odds ratio, 1.76 [1.03-3.00]; P=0.037), including lower left ventricular ejection fraction and a higher proportion of akinetic segments. CONCLUSIONS: Our findings define a mechanism for the profibrotic action of cardiac stromal cells through secreted cardiokines, such as GDF3, a candidate marker of adverse fibrotic remodeling after MI. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01113268.
dc.language.isoENen_US
dc.title.enNovel Cardiokine GDF3 Predicts Adverse Fibrotic Remodeling After Myocardial Infarction
dc.title.alternativeCirculationen_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1161/circulationaha.121.056272en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed36484260en_US
bordeaux.journalCirculationen_US
bordeaux.volume147en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - UMR 1219en_US
bordeaux.issue6en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.teamELEANOR_BPHen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03993736
hal.version1
hal.date.transferred2023-02-17T09:15:31Z
hal.exporttrue
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Circulation&rft.date=2023-02-07&rft.volume=147&rft.issue=6&rft.eissn=1524-4539%20(Electronic)%200009-7322%20(Linking)&rft.issn=1524-4539%20(Electronic)%200009-7322%20(Linking)&rft.au=MASURKAR,%20Nihar&BOUVET,%20Marion&LOGEART,%20Damien&JOUVE,%20Charlene&DRAME,%20Fatou&rft.genre=article


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