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Knockdown of AMPKα2 Promotes Pulmonary Arterial Smooth Muscle Cells Proliferation via mTOR/Skp2/p27Kip1 Signaling Pathway

Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA
Author to whom correspondence should be addressed.
Academic Editor: Atsushi Matsuzawa
Int. J. Mol. Sci. 2016, 17(6), 844;
Received: 4 March 2016 / Revised: 6 May 2016 / Accepted: 24 May 2016 / Published: 31 May 2016
(This article belongs to the Special Issue Kinase Signal Transduction)
PDF [2330 KB, uploaded 31 May 2016]


It has been shown that activation of adenosine monophosphate-activated protein kinase (AMPK) suppresses proliferation of a variety of tumor cells as well as nonmalignant cells. In this study, we used post-transcriptional gene silencing with small interfering RNA (siRNA) to specifically examine the effect of AMPK on pulmonary arterial smooth muscle cells (PASMCs) proliferation and to further elucidate its underlying molecular mechanisms. Our results showed that knockdown of AMPKα2 promoted primary cultured PASMCs proliferation; this was accompanied with the elevation of phosphorylation of mammalian target of rapamycin (mTOR) and S-phase kinase-associated protein 2 (Skp2) protein level and reduction of p27Kip1. Importantly, prior silencing of mTOR with siRNA abolished AMPKα2 knockdown-induced Skp2 upregulation, p27Kip1 reduction as well as PASMCs proliferation. Furthermore, pre-depletion of Skp2 by siRNA also eliminated p27Kip1 downregulation and PASMCs proliferation caused by AMPKα2 knockdown. Taken together, our study indicates that AMPKα2 isoform plays an important role in regulation of PASMCs proliferation by modulating mTOR/Skp2/p27Kip1 axis, and suggests that activation of AMPKα2 might have potential value in the prevention and treatment of pulmonary arterial hypertension. View Full-Text
Keywords: AMPK; pulmonary arterial smooth muscle cells; proliferation; mTOR; Skp2 AMPK; pulmonary arterial smooth muscle cells; proliferation; mTOR; Skp2

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Ke, R.; Liu, L.; Zhu, Y.; Li, S.; Xie, X.; Li, F.; Song, Y.; Yang, L.; Gao, L.; Li, M. Knockdown of AMPKα2 Promotes Pulmonary Arterial Smooth Muscle Cells Proliferation via mTOR/Skp2/p27Kip1 Signaling Pathway. Int. J. Mol. Sci. 2016, 17, 844.

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