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Mammalian target of rapamycin complex 2 (mTORC2) coordinates pulmonary artery smooth muscle cell metabolism, proliferation, and survival in pulmonary arterial hypertension.

ABSTRACT: Enhanced proliferation, resistance to apoptosis, and metabolic shift to glycolysis of pulmonary arterial vascular smooth muscle cells (PAVSMCs) are key pathophysiological components of pulmonary vascular remodeling in idiopathic pulmonary arterial hypertension (PAH). The role of the distinct mammalian target of rapamycin (mTOR) complexes mTORC1 (mTOR-Raptor) and mTORC2 (mTOR-Rictor) in PAVSMC proliferation and survival in PAH and their therapeutic relevance are unknown.Immunohistochemical and immunoblot analyses revealed that mTORC1 and mTORC2 pathways are markedly upregulated in small remodeled pulmonary arteries and isolated distal PAVSMCs from subjects with idiopathic PAH that have increased ATP levels, proliferation, and survival that depend on glycolytic metabolism. Small interfering RNA- and pharmacology-based analysis showed that although both mTORC1 and mTORC2 contribute to proliferation, only mTORC2 is required for ATP generation and survival of idiopathic PAH PAVSMCs. mTORC2 downregulated the energy sensor AMP-activated protein kinase, which led to activation of mTORC1-S6 and increased proliferation, as well as a deficiency of the proapoptotic protein Bim and idiopathic PAH PAVSMC survival. NADPH oxidase 4 (Nox4) protein levels were increased in idiopathic PAH PAVSMCs, which was necessary for mTORC2 activation, proliferation, and survival. Nox4 levels and mTORC2 signaling were significantly upregulated in small pulmonary arteries from hypoxia-exposed rats at days 2 to 28 of hypoxia. Treatment with the mTOR kinase inhibitor PP242 at days 15 to 28 suppressed mTORC2 but not Nox4, induced smooth muscle-specific apoptosis in small pulmonary arteries, and reversed hypoxia-induced pulmonary vascular remodeling in rats.These data provide a novel mechanistic link of Nox4-dependent activation of mTORC2 via the energy sensor AMP-activated protein kinase to increased proliferation and survival of PAVSMCs in PAH, which suggests a new potential pathway for therapeutic interventions.

SUBMITTER: Goncharov DA

PROVIDER: S-EPMC3968690 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Mammalian target of rapamycin complex 2 (mTORC2) coordinates pulmonary artery smooth muscle cell metabolism, proliferation, and survival in pulmonary arterial hypertension.

Goncharov Dmitry A DA Kudryashova Tatiana V TV Ziai Houman H Ihida-Stansbury Kaori K DeLisser Horace H Krymskaya Vera P VP Tuder Rubin M RM Kawut Steven M SM Goncharova Elena A EA

Circulation 20131122 8

<h4>Background</h4>Enhanced proliferation, resistance to apoptosis, and metabolic shift to glycolysis of pulmonary arterial vascular smooth muscle cells (PAVSMCs) are key pathophysiological components of pulmonary vascular remodeling in idiopathic pulmonary arterial hypertension (PAH). The role of the distinct mammalian target of rapamycin (mTOR) complexes mTORC1 (mTOR-Raptor) and mTORC2 (mTOR-Rictor) in PAVSMC proliferation and survival in PAH and their therapeutic relevance are unknown.<h4>Met ...[more]

PMID: 24270265

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Project description:Activation of the mammalian target of rapamycin complex 1 (mTORC1) subunit Raptor induces cell growth and is a downstream target of Akt. Elevated levels of aldosterone activate Akt, and, in pulmonary arterial hypertension (PAH), correlate with pulmonary arteriole thickening, which suggests that mTORC1 regulation by aldosterone may mediate adverse pulmonary vascular remodeling. We hypothesized that aldosterone-Raptor signaling induces abnormal pulmonary artery smooth muscle cell (PASMC) survival patterns to promote PAH. Remodeled pulmonary arterioles from SU-5416/hypoxia-PAH rats and monocrotaline-PAH rats with hyperaldosteronism expressed increased levels of the Raptor target, p70S6K, which provided a basis for investigating aldosterone-Raptor signaling in human PASMCs. Aldosterone (10(-9) to 10(-7) M) increased Akt/mTOR/Raptor to activate p70S6K and increase proliferation, viability, and apoptosis resistance in PASMCs. In PASMCs transfected with Raptor-small interfering RNA or treated with spironolactone/eplerenone, aldosterone or pulmonary arterial plasma from patients with PAH failed to increase p70S6K activation or to induce cell survival in vitro Optimal inhibition of pulmonary arteriole Raptor was achieved by treatment with Staramine-monomethoxy polyethylene glycol that was formulated with Raptor-small interfering RNA plus spironolactone in vivo, which decreased arteriole muscularization and pulmonary hypertension in 2 experimental animal models of PAH in vivo Up-regulation of mTORC1 by aldosterone is a critical pathobiologic mechanism that controls PASMC survival to promote hypertrophic vascular remodeling and PAH.-Aghamohammadzadeh, R., Zhang, Y.-Y., Stephens, T. E., Arons, E., Zaman, P., Polach, K. J., Matar, M., Yung, L.-M., Yu, P. B., Bowman, F. P., Opotowsky, A. R., Waxman, A. B., Loscalzo, J., Leopold, J. A., Maron, B. A. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension.

Project description:Background: We aimed to evaluate the expression of cysteine rich 61 (Cyr61) in patients with pulmonary arterial hypertension (PAH) as well as monocrotaline (MCT) induced PAH rat, and further investigate the effects and potential mechanisms of Cyr61 on the proliferation of pulmonary arterial smooth muscle cells (PASMCs). Methods and Results: Plasma samples were collected from 20 patients with idiopathic PAH, 20 connective tissue disease (CTD) associated PAH, 29 age-, gender- and disease matched CTD without PAH patients, and 28 healthy controls. ELISA was used to detect the level of Cyr61 in plasma. MCT-induced PAH (MCT-PAH) rat model was established by a single subcutaneous injection of MCT (60mg·kg-1). Lung tissues and pulmonary arteries of rats were collected, while the PASMCs were dissected and cultivated for in vitro experiments. Expression of Cyr61 in the lung tissues, pulmonary arteries and PASMCs were tested by immunohistochemical staining, western blot and quantitative real-time polymerase chain reaction. PASMCs from PAH rats were stimulated by exogenous recombinant Cyr61 protein and knocked down by small interfering RNA. Cell Counting Kit-8 assay was used to identify cell proliferation and the expression of p-AKT and AKT were analysed by western blot. The results showed plasma level of Cyr61 in PAH patients, especially CTD-PAH patients, were significant higher than that of CTD without PAH patients and healthy controls. Compared with wild rats, Cyr61 was overexpressed in the lung tissue, pulmonary arterial and PASMCs in PAH rats. Exogenous recombinant Cyr61 protein promoted the proliferation of PASMCs in a dose-dependent manner. While the expression of Cyr61 in PASMCs was inhibited by specific siRNA, cell proliferation was restrained and the expression of p-AKT declined. Conclusion: Plasma Cyr61 concentration in PAH patients was highly increased. Cyr61 could promote PASMCs proliferation via AKT pathway, indicating that Cyr61 may play a role in the pathogenesis of PAH.

Dataset Information

Mammalian target of rapamycin complex 2 (mTORC2) coordinates pulmonary artery smooth muscle cell metabolism, proliferation, and survival in pulmonary arterial hypertension.

Publications

Mammalian target of rapamycin complex 2 (mTORC2) coordinates pulmonary artery smooth muscle cell metabolism, proliferation, and survival in pulmonary arterial hypertension.

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