TY - JOUR
T1 - Modulation of transforming growth factor-β signaling and extracellular matrix production in myxomatous mitral valves by angiotensin II receptor blockers.
AU - Geirsson, Arnar
AU - Singh, Mansher
AU - Ali, Rahmat
AU - Abbas, Hussain
AU - Li, Wei
AU - Sanchez, Juan A.
AU - Hashim, Sabet
AU - Tellides, George
N1 - Copyright:
This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
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U2 - 10.1161/circulationaha.111.082610
DO - 10.1161/circulationaha.111.082610
M3 - Article
C2 - 22965982
AN - SCOPUS:84873271672
SN - 0009-7322
VL - 126
SP - S189-197
JO - Circulation
JF - Circulation
IS - 11 Suppl 1
ER -