Integrin-mediated mTOR signaling drives TGF-β overactivity and myxomatous mitral valve degeneration in hypomorphic fibrillin-1 mice.

Fu Gao,Qixin Chen,Makoto Mori,Sufang Li,Giovanni Ferrari,Markus Krane,Rong Fan,George Tellides,Yang Liu,Arnar Geirsson
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Abstract

Mitral valve prolapse is often benign but progression to mitral regurgitation may require invasive intervention and there is no specific medical therapy. An association of mitral valve prolapse with Marfan syndrome resulting from pathogenic FBN1 variants supports the use of hypomorphic fibrillin-1 mgR mice to investigate mechanisms and therapy for mitral valve disease. mgR mice developed severe myxomatous mitral valve degeneration with mitral regurgitation by 12 weeks of age. Persistent activation of TGF-β and mTOR signaling along with macrophage recruitment preceded histological changes at 4 weeks of age. Short-term mTOR inhibition with rapamycin from 4 to 5 weeks of age prevented TGF-β overactivity and leukocytic infiltrates, while long-term inhibition of mTOR or TGF-β signaling from 4 to 12 weeks of age rescued mitral valve leaflet degeneration. Transcriptomic analysis identified integrins as key receptors in signaling interactions and serologic neutralization of integrin signaling or a chimeric integrin receptor altering signaling prevented mTOR activation. We confirmed increased mTOR signaling and a conserved transcriptome signature in human specimens of sporadic mitral valve prolapse. Thus, mTOR activation from abnormal integrin-dependent cell-matrix interactions drives TGF-β overactivity and myxomatous mitral valve degeneration, and mTOR inhibition may prevent disease progression of mitral valve prolapse.
整合素介导的mTOR信号驱动TGF-β过度活性和二尖瓣黏液变性。
二尖瓣脱垂通常是良性的,但进展到二尖瓣反流可能需要侵入性干预,没有特异性的药物治疗。由致病性FBN1变异引起的二尖瓣脱垂与马凡氏综合征的关联支持了使用亚形态纤原蛋白-1 mgR小鼠来研究二尖瓣疾病的机制和治疗方法。mgR小鼠在12周龄时发生严重的二尖瓣黏液瘤变性并伴有二尖瓣反流。TGF-β和mTOR信号的持续激活以及巨噬细胞的募集先于4周龄的组织学变化。4 ~ 5周龄用雷帕霉素短期抑制mTOR可阻止TGF-β过度活跃和白细胞浸润,而4 ~ 12周龄长期抑制mTOR或TGF-β信号可挽救二尖瓣小叶变性。转录组学分析发现整合素是信号相互作用的关键受体,整合素信号的血清学中和或嵌合整合素受体改变信号阻止mTOR激活。我们在散发性二尖瓣脱垂的人类标本中证实了mTOR信号的增加和保守的转录组特征。因此,整合素依赖性细胞-基质相互作用异常引起的mTOR激活可驱动TGF-β过度活性和粘液瘤性二尖瓣变性,抑制mTOR可预防二尖瓣脱垂的疾病进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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