Activation of AMPK inhibits PDGF-induced pulmonary arterial smooth muscle cells proliferation and its potential mechanisms

Song, Yang; Wu, Yuanyuan; Su, Xiaofan; Zhu, Yanting; Liu, Lu; Pan, Yilin; Zhu, Bo; Yang, Lan; Gao, Li; Li, Manxiang

doi:10.1016/j.phrs.2016.03.010

Cited by 42 publications

(34 citation statements)

References 40 publications

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“…Metformin is an in vitro synthetic AMPK agonist which has been commonly used in clinic to treat type 2 diabetes with wide clinical experience and safety record [ 49 ]. We have recently found that activation of AMPKα2 by metformin suppresses PASMCs proliferation [ 50 ], together with our current findings, suggesting that metformin might be used in clinical treatment of PAH. Yet, this still needs to be tested in patients with PAH.…”

Section: Discussionsupporting

confidence: 86%

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

Rui

Liu

Zhu

et al. 2016

IJMS

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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.

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Section: Discussionsupporting

confidence: 86%

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

Rui

Liu

Zhu

et al. 2016

IJMS

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“…Several studies have shown that AMPK promotes SMC proliferation and the development of pulmonary hypertension, which was reversed with AMPK inhibition (Ibe et al, 2013;Moral-Sanz et al, 2016). Conversely, other studies have shown that AMPK activation reduced SMC proliferation and vascular remodeling and may be protective against the development of hypoxia-induced pulmonary hypertension (Agard et al, 2009;Dean et al, 2016;Song et al, 2016). Importantly, in our present study, hPASMC proliferation was decreased with AMPK activation by AICAR ( Figure 6).…”

Section: F I G U R Esupporting

confidence: 53%

“…Whereas NO acts as both a target and an effector of the AMPK pathway in endothelial cells (Fisslthaler & Fleming, 2009;Suzuki et al, 2008), less is known about the mechanism by which NO regulates AMPK in smooth muscle cells. Moreover, data on the role of AMPK in vascular proliferation and pulmonary hypertension are conflicting (Agard et al, 2009;Dean, Nilsen, Loughlin, Salt, & MacLean, 2016;Ibe et al, 2013;Moral-Sanz et al, 2016;Salt & Hardie, 2017;Song et al, 2016). Several studies have shown that AMPK promotes SMC proliferation and the development of pulmonary hypertension, which was reversed with AMPK inhibition (Ibe et al, 2013;Moral-Sanz et al, 2016).…”

Section: F I G U R Ementioning

confidence: 99%

Nitric oxide activates AMPK by modulating PDE3A in human pulmonary artery smooth muscle cells

et al. 2020

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Phosphodiesterase 3 (PDE3), of which there are two isoforms, PDE3A and PDE3B, hydrolyzes cAMP and cGMP—cyclic nucleotides important in the regulation of pulmonary vascular tone. PDE3 has been implicated in pulmonary hypertension unresponsive to nitric oxide (NO); however, contributions of the two isoforms are not known. Furthermore, adenosine monophosphate‐activated protein kinase (AMPK), a critical regulator of cellular energy homeostasis, has been shown to be modulated by PDE3 in varying cell types. While AMPK has recently been implicated in pulmonary hypertension pathogenesis, its role and regulation in the pulmonary vasculature remain to be elucidated. Therefore, we utilized human pulmonary artery smooth muscle cells (hPASMC) to test the hypothesis that NO increases PDE3 expression in an isoform‐specific manner, thereby activating AMPK and inhibiting hPASMC proliferation. We found that in hPASMC, NO treatment increased PDE3A protein expression and PDE3 activity with a concomitant decrease in cAMP concentrations and increase in AMPK phosphorylation. Knockdown of PDE3A using siRNA transfection blunted the NO‐induced AMPK activation, indicating that PDE3A plays an important role in AMPK regulation in hPASMC. Treatment with a soluble guanylate cyclase (sGC) stimulator increased PDE3A expression and AMPK activation similar to that seen with NO treatment, whereas treatment with a sGC inhibitor blunted the NO‐induced increase in PDE3A and AMPK activation. These results suggest that NO increases PDE3A expression, decreases cAMP, and activates AMPK via the sGC‐cGMP pathway. We speculate that NO‐induced increases in PDE3A and AMPK may have implications in the pathogenesis and the response to therapies in pulmonary hypertensive disorders.

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“…Our ssGSEA/GSEA analysis showed that the "metformin_downregulated" signature and NFkB signaling exhibited a good consistency with the activated stromal fibroblast phenotype corresponding to the acknowledged pathway characteristically activated in CAFs (46) such as TGFb, IGF1/PI3K/mTOR, PDGF, and the JAK/STAT signaling. Actually, all these signaling factors associated with CAFs activation have been reported to be inhibited by metformin in fibroblasts or other cells (23,45,54,60,61). These preliminary results indicate that metformin will likely exert a multiple reprogramming of CAFs in ovarian cancer.…”

Section: Discussionmentioning

confidence: 71%

Metformin Suppresses Tumor Progression by Inactivating Stromal Fibroblasts in Ovarian Cancer

Yang

Park

et al. 2018

Molecular Cancer Therapeutics

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Ovarian cancer is a devastating disease due to its high incidence of relapse and chemoresistance. The tumor microenvironment, especially the tumor stroma compartment, was proven to contribute tremendously to the unsatisfactory chemotherapeutic efficacy in ovarian cancer. Cytotoxic agents not only effect tumor cells, but also modulate the phenotype and characteristics of the vast stromal cell population, which can in turn alter the tumor cell response to chemointervention. In this study, we focused on the tumor stroma response to cytotoxic agents and the subsequent effect on the ovarian cancer tumor cells. First, we found a significant stromal overexpression of IL6 in patient samples that received cisplatin-based treatment, which was further validated in purified fibroblasts challenged with cisplatin. Stromal fibroblast-derived IL6 was proven to mediate ovarian cancer tumor cell chemoresistance. For the first time, we found that the tumor stroma of patients with routine metformin administration exhibited lower IL6 expression. Thus, we presumed that metformin was a potent alleviator of stromal inflammation in ovarian cancer. We found that metformin partly reversed cisplatin-stimulated IL6 secretion in the stromal fibroblasts and attenuated fibroblast-facilitated tumor growth in 3D organotypic cocultures and murine xenograft models. Mechanistically, we found that metformin inhibited IL6 secretion via suppressing NFκB signaling, an upstream controller of stromal inflammation. Collectively, our findings introduced a novel mechanism of metformin in suppressing ovarian cancer progression through diminishing chemotherapy-induced stromal activation. Therefore, we provide an alternative therapeutic option in targeting stromal inflammation and a potential scheme of combination therapy to improve the chemosensitivity in ovarian cancer. .

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Activation of AMPK inhibits PDGF-induced pulmonary arterial smooth muscle cells proliferation and its potential mechanisms

Cited by 42 publications

References 40 publications

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

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

Nitric oxide activates AMPK by modulating PDE3A in human pulmonary artery smooth muscle cells

Metformin Suppresses Tumor Progression by Inactivating Stromal Fibroblasts in Ovarian Cancer

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