Modulation of Transforming Growth Factor-β Signaling and Extracellular Matrix Production in Myxomatous Mitral Valves by Angiotensin II Receptor Blockers
Modulation of Transforming Growth Factor-β Signaling and Extracellular Matrix Production in Myxomatous Mitral Valves by Angiotensin II Receptor Blockers
复制标题
DOI：
10.1161/circulationaha.111.082610
复制
发表时间：
2012-09-11
期刊：
影响因子：
37.8
通讯作者：
Tellides, George
中科院分区：
文献类型：
--
作者：
Geirsson, Arnar;Singh, Mansher;Tellides, George
背景-二尖瓣粘液瘤样变性的病理生理学知之甚少，粘液瘤样变性是二尖瓣脱垂的病理标志，与症状性二尖瓣返流、心力衰竭和死亡相关。已知过量的转化生长因子（TGF）-β信号传导在马凡氏综合征小鼠模型中引起二尖瓣退化和反流。我们检查了与未患病的二尖瓣相比，在散发性二尖瓣脱垂的临床标本中TGF-β信号传导是否失调，并且我们测试了血管紧张素II受体阻断剂对培养的人二尖瓣细胞中TGF-β信号传导的影响。培养的瓣膜间质细胞得自进行二尖瓣修复的二尖瓣脱垂患者或无二尖瓣疾病的器官供体。病变瓣膜组织中细胞外基质的增加与TGF-β表达和信号传导的上调相关，如SMAD 2/3磷酸化所证明的。TGF-β配体和信号传导介质主要共定位于瓣膜间质细胞，表明自分泌/旁分泌激活。在培养的瓣膜组织中，外源性TGF-β增加了基础细胞外基质的产生，而TGF-β的血清学中和抑制了疾病驱动的细胞外基质过度产生。TGF-β诱导的细胞外基质的生产在培养的瓣膜间质细胞依赖于SMAD 2/3和p38信号转导和抑制血管紧张素II受体阻滞剂。结论-TGF-β具有促纤维化的作用，在发病机制中散发性二尖瓣脱垂。血管紧张素II受体阻滞剂减弱TGF-β信号传导可能是调节患者二尖瓣脱垂病理进展的机制性策略。（循环。2012;126[suppl 1]：S189-S197.）
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)-beta signaling is known to cause mitral valve degeneration and regurgitation in a mouse model of Marfan syndrome. We examined if TGF-beta 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-beta signaling in cultured human mitral valve cells.Methods and 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-beta expression and signaling as evidenced by SMAD2/3 phosphorylation. Both TGF-beta ligand and signaling mediators colocalized primarily to valvular interstitial cells suggesting autocrine/paracrine activation. In cultured valve tissue, exogenous TGF-beta increased basal extracellular matrix production, whereas serological neutralization of TGF-beta inhibited disease-driven extracellular matrix overproduction. TGF-beta-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-beta has a profibrotic role in the pathogenesis of sporadic mitral valve prolapse. Attenuation of TGF-beta signaling by angiotensin II receptor blockers may represent a mechanistically based strategy to modulate the pathological progression of mitral valve prolapse in patients. (Circulation. 2012;126[suppl 1]:S189-S197.)