title: Modulation of transforming growth factor-β signaling and extracellular matrix production in myxomatous mitral valves by angiotensin II receptor blockers.
abstract: BACKGROUND
  Little 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Section of Cardiac Surgery, Yale University School of Medicine, 330 Cedar Street, BB204, PO Box 208039, New Haven, CT 06520-8039, USA. arnar.geirsson@yale.edu
authors.forename: Arnar
authors.initials: A
authors.lastname: Geirsson
authors.forename: Mansher
authors.initials: M
authors.lastname: Singh
authors.forename: Rahmat
authors.initials: R
authors.lastname: Ali
authors.forename: Hussain
authors.initials: H
authors.lastname: Abbas
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Juan A
authors.initials: JA
authors.lastname: Sanchez
authors.forename: Sabet
authors.initials: S
authors.lastname: Hashim
authors.forename: George
authors.initials: G
authors.lastname: Tellides
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001713:Biphenyl Compounds; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D004547:Elastic Tissue / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000235:genetics; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects*; D040181:Genetic Diseases, X-Linked / Q000150:complications / Q000378:metabolism / Q000473:pathology; D006330:Heart Defects, Congenital / Q000150:complications / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019808:Losartan / Q000494:pharmacology; D008944:Mitral Valve Insufficiency / Q000209:etiology / Q000601:surgery; D008945:Mitral Valve Prolapse / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D009232:Myxoma / Q000150:complications / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000502:physiology; D051900:Smad3 Protein / Q000502:physiology; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014746:Vimentin / Q000096:biosynthesis / Q000235:genetics
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001565:Benzoates; D001713:Biphenyl Compounds; D016326:Extracellular Matrix Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D014746:Vimentin; D003094:Collagen; D019808:Losartan; C081643:candesartan; D000077333:Telmisartan