1. Selective Tuberous Sclerosis Complex 1 Gene Deletion in Smooth Muscle Activates Mammalian Target of Rapamycin Signaling and Induces Pulmonary Hypertension
- Author
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Shariq Abid, Larissa Lipskaia, Valérie Amsellem, Geneviève Derumeaux, Caroline Treins, Feng Wan, Daigo Sawaki, Amal Houssaini, Jean-Luc Dubois-Randé, Dominique Rideau, Serge Adnot, Zhenlin Li, Aurélien Parpaleix, Elisabeth Marcos, Mario Pende, Gabor Czibik, Kanny Kebe, Génétique et Physiopathologie des Tissus Musculaires (GPTM), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INSERM, Ministere de la Recherche, Delegation a la Recherche Clinique de l'AP-HP, Fondation pour la Recherche Medicale, Chancellerie des Universites de Paris (Legs Poix), Fondation Coeur et Poumon, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,0301 basic medicine ,Pathology ,[SDV]Life Sciences [q-bio] ,Clinical Biochemistry ,Muscle Proteins ,mTORC1 ,mTORC2 ,Tuberous Sclerosis Complex 1 Protein ,smooth muscle ,Mice ,GSK-3 ,pulmonary hypertension ,Hypoxia ,Lung ,Cells, Cultured ,Kinase ,TOR Serine-Threonine Kinases ,Microfilament Proteins ,Metformin ,medicine.anatomical_structure ,biological phenomena, cell phenomena, and immunity ,Signal Transduction ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Hypertension, Pulmonary ,Myocytes, Smooth Muscle ,Cre recombinase ,Pulmonary Artery ,Biology ,Ribosomal Protein S6 Kinases, 90-kDa ,03 medical and health sciences ,medicine ,Animals ,Molecular Biology ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Sirolimus ,Hyperplasia ,rapamycin ,Tumor Suppressor Proteins ,Muscle, Smooth ,Cell Biology ,medicine.disease ,Pulmonary hypertension ,Molecular biology ,030104 developmental biology ,Chronic Disease ,TSC1 ,Gene Deletion - Abstract
International audience; Constitutive activation of the mammalian target of rapamycin (mTOR) complexes mTORC1 and mTORC2 is associated with pulmonary hypertension (PH) and sustained growth of pulmonary artery (PA) smooth muscle cells (SMCs). We investigated whether selective mTORC1 activation in SMCs induced by deleting the negative mTORC1 regulator tuberous sclerosis complex 1 gene (TSC1) was sufficient to produce PH in mice. Mice expressing Cre recombinase under SM22 promoter control were crossed with TSC1(LoxP/LoxP) mice to generate SM22-TSC1(-/-) mice. At 8weeks of age, SM22-TSC1(-/-) mice exhibited PH with marked increases in distal PA muscularization and Ki67-positive PASMC counts, without systemic hypertension or cardiac dysfunction. Marked activation of the mTORC1 substrates S6 kinase and 4E-BP and the mTORC2 substrates p-Akt(Ser473) and glycogen synthase kinase 3 was found in the lungs and pulmonary vessels of SM22-TSC1(-/-) mice when compared with control mice. Treatment with 5 mg/kg rapamycin for 3 weeks to inhibit mTORC1 and mTORC2 fully reversed PH in SM22-TSC1(-/-) mice. In chronically hypoxic mice and SM22-5HTT(+) mice exhibiting PH associated with mTORC1 and mTORC2 activation, PH was maximally attenuated by low-dose rapamycin associated with selective mTORC1 inhibition. Cultured PASMCs from SM22-TSC1(-/-), SM22-5HTT(+,) and chronically hypoxicmice exhibited similar sustained growth-rate enhancement and constitutive mTORC1 and mTORC2 activation; both effects were abolished by rapamycin. Deletion of the downstream mTORC1 effectors S6 kinase 1/2 in mice also activated mTOR signaling and induced PH. We concluded that activation of mTORC1 signaling leads to increased PASMC proliferation and subsequent PH development.
- Published
- 2016
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