Selective TSC1 deletion in smooth muscle results in mTOR signaling activation and development of pulmonary hypertension that can be reversed by rapamycin - 04/04/15
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Résumé |
Background |
Pulmonary artery (PA) smooth muscle cell (SMC) proliferation in pulmonary hypertension (PH) is associated with dysregulated mammalian target of rapamycin (mTOR) signaling. The mTOR pathway involves two independent complexes, mTORC1 and mTORC2, which phosphorylate S6 kinase (S6K) and serine/threonine kinase (Akt), respectively, and differ in their sensitivity to rapamycin. Here, we investigated whether selective mTOR activation in SMCs was sufficient to induce PH in mice.
Methods |
To selectively activate the mTOR-S6K pathway in SMCs, we developed mice with selective deletion in SMCs of the tuberous sclerosis complex 1 gene (TSC1), which negatively controls mTOR, by crossing TSC1LoxP/LoxP mice with mice expressing the Cre recombinase under the control of the SM22alpha promoter (SM22/TSC1-/− mice).
Results |
SM22/TSC1-/− mice had increased body and heart weights with normal survival at 1year of age. Echocardiography showed normal left ventricle (LV) size and ejection fraction but increased anterior and posterior wall thicknesses. Right ventricle (RV) and LV weights were increased and the RV/LV+septum weight ratio markedly elevated. Marked activation of the mTOR-Akt signaling pathway was found in lungs from SM22/TSC1-/− mice compared to controls, with a marked PTEN decrease and activation of mTORC1 substrates S6K and 4EBP and of mTORC2 substrates P-AktSer473 and GSK3. In situ analysis of lung specimens revealed prominent P-Akt, P-S6K, and P-GSK3 staining in PA-SMCs. SM22/TSC1-/− mice spontaneously developed PH due to pulmonary vascular remodeling, as assessed by increased RV systolic pressure, muscularization of distal pulmonary arteries, and increased number of Ki67-positive dividing pulmonary vascular cells. Treatment with 5mg/Kg rapamycin during 3 weeks reversed PH and reduced lung P-Akt, P-S6K, and P-GSK3 proteins to control levels. Cultured PA-SMCs from SM22/TSC1-/− mice exhibited an increased growth rate and sustained activation of mTORC1 and mTORC2 substrates compared to controls. PA-SMC exposure to rapamycin inhibited the serum-induced growth and diminished the difference in growth rate between cells from SM22/TSC1-/− and WT mice.
Conclusion |
These results support a critical role in PH for mTOR signaling pathway activation, which can be suppressed by rapamycin treatment.
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Vol 32 - N° 3
P. 326 - mars 2015 Retour au numéro
Article précédent
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