mTOR signal in mitral valve diseases

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. Single cell RNA sequence by 10x, mgR/mgR mice, as well as their respective wild type controls Fbn1+/+ (+/+))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。在模拟马方综合征的功能低下型Fbn1突变mgR小鼠中，黏液样二尖瓣变性与二尖瓣反流可在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，以及巨噬细胞浸润，可在组织学改变出现前的4周龄时被检测到。短期雷帕霉素给药可阻断早期TGF-β激活与炎症反应，而长期抑制mTOR或TGF-β则可逆转瓣膜变性进程。转录组学分析显示，整合素是mTOR的上游调控因子。阻断整合素信号通路或调控其通路活性，可抑制mTOR的激活。上述研究结果在人类二尖瓣脱垂中同样保守存在，提示通过异常整合素-基质信号通路激活的mTOR是疾病驱动因素，且mTOR抑制疗法或可成为潜在治疗方案。本研究的单细胞RNA测序采用10x Genomics平台，样本包括mgR/mgR小鼠及其对应的野生型对照Fbn1+/+（+/+）小鼠。