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mTOR is required for pulmonary arterial vascular smooth muscle cell proliferation under chronic hypoxia
Author(s) -
Krymskaya Vera P.,
Snow Jennifer,
Cesarone Gregory,
Khavin Irene,
Goncharov Dmitry A.,
Lim Poay N.,
Veasey Sigrid C.,
IhidaStansbury Kaori,
Jones Peter L.,
Goncharova Elena A.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-175018
Subject(s) - mtorc2 , pi3k/akt/mtor pathway , mtorc1 , protein kinase b , vascular smooth muscle , hypoxia (environmental) , cell growth , mechanistic target of rapamycin , phosphorylation , microbiology and biotechnology , rptor , biology , cancer research , chemistry , signal transduction , endocrinology , biochemistry , organic chemistry , smooth muscle , oxygen
Pulmonary arterial vascular smooth muscle (PAVSM) cell proliferation is a key pathophysi‐ological 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 nor‐moxia‐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.—Krymskaya, V. P., Snow, J., Cesarone, G., Khavin, I., Goncharov, D. A., Lim, P. N., Veasey, S. C, Ihida‐Stansbury, K., Jones, P. L., Goncharova, E. A. mTOR is required for pulmonary arterial vascular smooth muscle cell proliferation under chronic hypoxia. FASEB J. 25, 1922‐1933 (2011). www.fasebj.org