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 mutations—mimicking Marfan syndrome—myxomatous mitral degeneration and regurgitation develop by 12 weeks. TGF-ß and mTOR signaling activation, along with macrophage infiltration, appear by 4 weeks, before histological changes. Short-term rapamycin treatment blocks early TGF-ß activation and inflammation, while long-term mTOR or TGF-ß 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. Overall design: Single cell RNA sequence by 10x, mgR/mgR mice, as well as their respective wild type controls Fbn1+/+ (+/+))