Modulation of transforming growth factor-β signaling and extracellular matrix production in myxomatous mitral valves by angiotensin II receptor blockers.

Arnar Geirsson, Mansher Singh, Rahmat Ali, Hussain Abbas, Wei Li, Juan Sanchez, Sabet Hashim, George Tellides

Research output: Contribution to journalArticle

Abstract

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. 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.

Original languageEnglish (US)
JournalCirculation
Volume126
Issue number11 Suppl 1
StatePublished - Sep 11 2012
Externally publishedYes

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Angiotensin Receptor Antagonists
Transforming Growth Factors
Mitral Valve
Extracellular Matrix
Mitral Valve Prolapse
Mitral Valve Insufficiency
Marfan Syndrome
Up-Regulation
Heart Failure
Phosphorylation
Tissue Donors
Ligands

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Modulation of transforming growth factor-β signaling and extracellular matrix production in myxomatous mitral valves by angiotensin II receptor blockers. / Geirsson, Arnar; Singh, Mansher; Ali, Rahmat; Abbas, Hussain; Li, Wei; Sanchez, Juan; Hashim, Sabet; Tellides, George.

In: Circulation, Vol. 126, No. 11 Suppl 1, 11.09.2012.

Research output: Contribution to journalArticle

Geirsson, Arnar ; Singh, Mansher ; Ali, Rahmat ; Abbas, Hussain ; Li, Wei ; Sanchez, Juan ; Hashim, Sabet ; Tellides, George. / Modulation of transforming growth factor-β signaling and extracellular matrix production in myxomatous mitral valves by angiotensin II receptor blockers. In: Circulation. 2012 ; Vol. 126, No. 11 Suppl 1.
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