Show simple item record

dc.contributor.authorGeirsson, Arnar
dc.contributor.authorSingh, Mansher
dc.contributor.authorAli, Rahmat
dc.contributor.authorAbbas, Hussain
dc.contributor.authorLi, Wei
dc.contributor.authorSanchez, Juan A
dc.contributor.authorHashim, Sabet
dc.contributor.authorTellides, George
dc.date.accessioned2013-08-16T11:44:23Z
dc.date.available2013-08-16T11:44:23Z
dc.date.issued2012-09-11
dc.date.submitted2013-08-16
dc.identifier.citationCirculation 2012, 126(11 Suppl 1):S189-97en_GB
dc.identifier.issn1524-4539
dc.identifier.pmid22965982
dc.identifier.doi10.1161/CIRCULATIONAHA.111.082610
dc.identifier.urihttp://hdl.handle.net/2336/298973
dc.description.abstractLittle is known about the pathophysiology of myxomatous degeneration of the mitral valve, the pathological hallmark of mitral valve prolapse, associated with symptomatic mitral regurgitation, heart failure, and death. Excess transforming growth factor (TGF)-β signaling is known to cause mitral valve degeneration and regurgitation in a mouse model of Marfan syndrome. We examined if TGF-β signaling is dysregulated in clinical specimens of sporadic mitral valve prolapse compared with explanted nondiseased mitral valves and we tested the effects of angiotensin II receptor blockers on TGF-β signaling in cultured human mitral valve cells. Operative specimens, cultured valve tissues, and cultured valvular interstitial cells were obtained from patients with mitral valve prolapse undergoing mitral valve repair or from organ donors without mitral valve disease. Increased extracellular matrix in diseased valve tissue correlated with an upregulation of TGF-β expression and signaling as evidenced by SMAD2/3 phosphorylation. Both TGF-β ligand and signaling mediators colocalized primarily to valvular interstitial cells suggesting autocrine/paracrine activation. In cultured valve tissue, exogenous TGF-β increased basal extracellular matrix production, whereas serological neutralization of TGF-β inhibited disease-driven extracellular matrix overproduction. TGF-β-induced extracellular matrix production in cultured valvular interstitial cells was dependent on SMAD2/3 and p38 signaling and was inhibited by angiotensin II receptor blockers. TGF-β has a profibrotic role in the pathogenesis of sporadic mitral valve prolapse. Attenuation of TGF-β signaling by angiotensin II receptor blockers may represent a mechanistically based strategy to modulate the pathological progression of mitral valve prolapse in patients.
dc.language.isoenen
dc.relation.urlhttp://dx.doi.org/10.1161/CIRCULATIONAHA.111.082610en_GB
dc.relation.urlhttp://ovidsp.tx.ovid.com/sp-3.9.1a/ovidweb.cgi?T=JS&PAGE=fulltext&D=ovft&AN=00003017-201209111-00027&NEWS=N&CSC=Y&CHANNEL=PubMeden_GB
dc.rightsArchived with thanks to Circulationen_GB
dc.subject.meshAngiotensin Receptor Antagonistsen_GB
dc.subject.meshBenzimidazolesen_GB
dc.subject.meshBenzoatesen_GB
dc.subject.meshCells, Cultureden_GB
dc.subject.meshCollagenen_GB
dc.subject.meshElastic Tissueen_GB
dc.subject.meshExtracellular Matrix Proteinsen_GB
dc.subject.meshFibrosisen_GB
dc.subject.meshGene Expression Regulationen_GB
dc.subject.meshGenetic Diseases, X-Linkeden_GB
dc.subject.meshHeart Defects, Congenitalen_GB
dc.subject.meshHumansen_GB
dc.subject.meshLosartanen_GB
dc.subject.meshMitral Valve Insufficiencyen_GB
dc.subject.meshMitral Valve Prolapseen_GB
dc.subject.meshMyxomaen_GB
dc.subject.meshPolymerase Chain Reactionen_GB
dc.subject.meshSignal Transductionen_GB
dc.subject.meshSmad2 Proteinen_GB
dc.subject.meshSmad3 Proteinen_GB
dc.subject.meshTetrazolesen_GB
dc.subject.meshTransforming Growth Factor betaen_GB
dc.subject.meshVimentinen_GB
dc.titleModulation of transforming growth factor-β signaling and extracellular matrix production in myxomatous mitral valves by angiotensin II receptor blockers.en
dc.typeArticleen
dc.contributor.departmentSection of Cardiac Surgery, Yale University School of Medicine, 330 Cedar Street, BB204, PO Box 208039, New Haven, CT 06520-8039, USA. arnar.geirsson@yale.eduen_GB
dc.identifier.journalCirculationen_GB
dc.rights.accessLandspitali Access - LSH-aðganguren
html.description.abstractLittle is known about the pathophysiology of myxomatous degeneration of the mitral valve, the pathological hallmark of mitral valve prolapse, associated with symptomatic mitral regurgitation, heart failure, and death. Excess transforming growth factor (TGF)-β signaling is known to cause mitral valve degeneration and regurgitation in a mouse model of Marfan syndrome. We examined if TGF-β signaling is dysregulated in clinical specimens of sporadic mitral valve prolapse compared with explanted nondiseased mitral valves and we tested the effects of angiotensin II receptor blockers on TGF-β signaling in cultured human mitral valve cells. Operative specimens, cultured valve tissues, and cultured valvular interstitial cells were obtained from patients with mitral valve prolapse undergoing mitral valve repair or from organ donors without mitral valve disease. Increased extracellular matrix in diseased valve tissue correlated with an upregulation of TGF-β expression and signaling as evidenced by SMAD2/3 phosphorylation. Both TGF-β ligand and signaling mediators colocalized primarily to valvular interstitial cells suggesting autocrine/paracrine activation. In cultured valve tissue, exogenous TGF-β increased basal extracellular matrix production, whereas serological neutralization of TGF-β inhibited disease-driven extracellular matrix overproduction. TGF-β-induced extracellular matrix production in cultured valvular interstitial cells was dependent on SMAD2/3 and p38 signaling and was inhibited by angiotensin II receptor blockers. TGF-β has a profibrotic role in the pathogenesis of sporadic mitral valve prolapse. Attenuation of TGF-β signaling by angiotensin II receptor blockers may represent a mechanistically based strategy to modulate the pathological progression of mitral valve prolapse in patients.


This item appears in the following Collection(s)

Show simple item record