mTOR signal in mitral valve diseases II

Mitral valve prolapse (MVP) is often benign but can progress to mitral regurgitation, requiring invasive treatment. In mgR mice with hypomorphic Fbn1 mutationsmimicking Marfan syndromemyxomatous mitral degeneration and regurgitation develop by 12 weeks. TGF- and mTOR signaling activation, along with macrophage infiltration, appear by 4 weeks, before histological changes. Short-term rapamycin treatment blocks early TGF- activation and inflammation, while long-term mTOR or TGF- inhibition rescues valve degeneration. Transcriptomics revealed integrins as upstream regulators of mTOR. Blocking integrin signaling or altering its pathway prevented mTOR activation. These findings are conserved in human MVP, suggesting that mTOR activation via abnormal integrin-matrix signaling drives disease and that mTOR inhibition may be a potential therapy.二尖瓣脱垂（Mitral valve prolapse, MVP）通常呈良性病程，但可进展为二尖瓣反流，需接受侵入性治疗。在携带模拟马方综合征（Marfan syndrome）的功能低下型Fbn1突变的mgR小鼠中，黏液样二尖瓣变性与二尖瓣反流于12周龄时出现。转化生长因子-β（TGF-β）与哺乳动物雷帕霉素靶蛋白（mTOR）信号通路激活，伴随巨噬细胞浸润，可在组织学改变出现前的4周龄时被检测到。短期雷帕霉素（rapamycin）治疗可阻断早期TGF-β激活与炎症反应，而长期mTOR或TGF-β抑制则可逆转瓣膜变性进程。转录组学（transcriptomics）分析显示，整合素（integrins）是mTOR的上游调控因子。阻断整合素信号通路或调控其通路可抑制mTOR激活。上述研究结果在人类二尖瓣脱垂中具有保守性，提示通过异常整合素-基质信号通路激活的mTOR信号是疾病驱动因素，且mTOR抑制或许可成为潜在治疗手段。