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MTOR is required for pulmonary arterial vascular smooth muscle cell proliferation under chronic hypoxia.

ABSTRACT: Pulmonary arterial vascular smooth muscle (PAVSM) cell proliferation is a key pathophysiological component of vascular remodeling in pulmonary arterial hypertension (PAH) for which cellular and molecular mechanisms are poorly understood. The goal of our study was to determine the role of mammalian target of rapamycin (mTOR) in PAVSM cell proliferation, a major pathological manifestation of vascular remodeling in PAH. Our data demonstrate that chronic hypoxia promoted mTOR(Ser-2481) phosphorylation, an indicator of mTOR intrinsic catalytic activity, mTORC1-specific S6 and mTORC2-specific Akt (Ser-473) phosphorylation, and proliferation of human and rat PAVSM cells that was inhibited by siRNA mTOR. PAVSM cells derived from rats exposed to chronic hypoxia (VSM-H cells) retained increased mTOR(Ser-2481), S6, Akt (Ser-473) phosphorylation, and DNA synthesis compared to cells from normoxia-exposed rats. Suppression of mTORC2 signaling with siRNA rictor, or inhibition of mTORC1 signaling with rapamycin and metformin, while having little effect on other complex activities, inhibited VSM-H and chronic hypoxia-induced human and rat PAVSM cell proliferation. Collectively, our data demonstrate that up-regulation of mTOR activity and activation of both mTORC1 and mTORC2 are required for PAVSM cell proliferation induced by in vitro and in vivo chronic hypoxia and suggest that mTOR may serve as a potential therapeutic target to inhibit vascular remodeling in PAH.

SUBMITTER: Krymskaya VP

PROVIDER: S-EPMC3101038 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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mTOR is required for pulmonary arterial vascular smooth muscle cell proliferation under chronic hypoxia.

Krymskaya Vera P VP Snow Jennifer J Cesarone Gregory G Khavin Irene I Goncharov Dmitry A DA Lim Poay N PN Veasey Sigrid C SC Ihida-Stansbury Kaori K Jones Peter L PL Goncharova Elena A EA

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20110302 6

Pulmonary arterial vascular smooth muscle (PAVSM) cell proliferation is a key pathophysiological component of vascular remodeling in pulmonary arterial hypertension (PAH) for which cellular and molecular mechanisms are poorly understood. The goal of our study was to determine the role of mammalian target of rapamycin (mTOR) in PAVSM cell proliferation, a major pathological manifestation of vascular remodeling in PAH. Our data demonstrate that chronic hypoxia promoted mTOR(Ser-2481) phosphorylati ...[more]

PMID: 21368105

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Project description:Rationale: Glycolytic shift is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). It remains unknown how glycolysis is increased and how increased glycolysis contributes to pulmonary vascular remodeling in PAH.Objectives: To determine whether increased glycolysis is caused by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and how PFKFB3-driven glycolysis induces vascular remodeling in PAH.Methods: PFKFB3 levels were measured in pulmonary arteries of patients and animals with PAH. Lactate levels were assessed in lungs of animals with PAH and in pulmonary artery smooth muscle cells (PASMCs). Genetic and pharmacologic approaches were used to investigate the role of PFKFB3 in PAH.Measurements and Main Results: Lactate production was elevated in lungs of PAH rodents and in platelet-derived growth factor-treated PASMCs. PFKFB3 protein was higher in pulmonary arteries of patients and rodents with PAH, in PASMCs of patients with PAH, and in platelet-derived growth factor-treated PASMCs. PFKFB3 inhibition by genetic disruption and chemical inhibitor attenuated phosphorylation/activation of extracellular signal-regulated kinase (ERK1/2) and calpain-2, and vascular remodeling in PAH rodent models, and reduced platelet-derived growth factor-induced phosphorylation/activation of ERK1/2 and calpain-2, collagen synthesis and proliferation of PASMCs. ERK1/2 inhibition attenuated phosphorylation/activation of calpain-2, and vascular remodeling in Sugen/hypoxia PAH rats, and reduced lactate-induced phosphorylation/activation of calpain-2, collagen synthesis, and proliferation of PASMCs. Calpain-2 inhibition reduced lactate-induced collagen synthesis and proliferation of PASMCs.Conclusions: Upregulated PFKFB3 mediates collagen synthesis and proliferation of PASMCs, contributing to vascular remodeling in PAH. The mechanism is through the elevation of glycolysis and lactate that results in the activation of calpain by ERK1/2-dependent phosphorylation of calpain-2.

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MTOR is required for pulmonary arterial vascular smooth muscle cell proliferation under chronic hypoxia.

Publications

mTOR is required for pulmonary arterial vascular smooth muscle cell proliferation under chronic hypoxia.

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