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Activation of AMPK inhibits Galectin-3-induced pulmonary artery smooth muscle cells proliferation by upregulating hippo signaling effector YAP

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Abstract

Galectin-3(Gal-3) is an effective regulator in the pathological process of pulmonary arterial hypertension (PAH). However, the detailed mechanisms underlying Gal-3 contribution to PAH are not yet entirely clear. The aim of the present study was to explore these issues. Proliferation of rat pulmonary arterial smooth muscle cells (PASMCs) was determined using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Small interfering RNA (siRNA) was applied to silence the expression of yes-associated protein (YAP) and Forkhead box M1 (FOXM1). The protein expression and phosphorylation were measured by immunoblotting. The subcellular location of YAP was determined using immunoblotting and immunofluorescence. Gal-3-stimulated PASMCs proliferation in a time- and dose-dependent manner, this was accompanied with, YAP upregulation, dephosphorylation, and nucleus translocation. Gal-3 further increased FOXM1 and cyclinD1 expression via YAP activation. Interfering YAP/FOXM1 axis suppressed Gal-3-induced PASMCs proliferation. Activation of AMPK also inhibited Gal-3-triggered cells proliferation by targeting YAP/FOXM1/cyclinD1 pathway. Gal-3 induced PASMCs proliferation by regulating YAP/FOXM1/cyclinD1 signaling cascade, and activation of AMPK targeted on this axis and suppressed Gal-3-stimulated PASMCs proliferation. Our study provides novel therapeutic targets for prevention and treatment of PAH.

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Data availability

Data will be made available on reasonable request.

Abbreviations

Gal-3:

Galectin-3

PAH:

Pulmonary arterial hypertension

PASMCs:

Pulmonary arterial smooth muscle cells

siRNA:

Small interfering RNA

YAP:

Yes-associated protein

FOXM1:

Forkhead box M1

AMPK:

Metformin-activated adenosine monophosphate-activated protein kinase

LATS1/2:

Large tumor suppressor kinase (LATS1/2)

PBS:

Phosphate-buffered saline

MTT:

3-(4, 5-Dimethylthiazol-2-yl)-2, 5- diphenyltetrazolium bromide

SEM:

Standard error of the mean

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Funding

This work was supported by the National Natural Science Foundation of China (Grant Numbers 81970050).

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Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xian Jiaotong University, Xi’an, 710061, Shaanxi, People’s Republic of China

    Qianqian Zhang, Qingting Wang, Cui Zhai, Wenhua Shi, Wei Feng, Jian Wang, Xin Yan, Limin Chai, Yuqian Chen, Cong Li, Pengtao Liu & Manxiang Li

  2. Department of Respiratory and Critical Care Medicine, The First Hospital of Weinan, Weinan, 714000, Shaanxi, People’s Republic of China

    Wenge Li

  3. Center of Nephropathy and Hemodialysis, Shaanxi Provincial People’s Hospital, Xi’an, 710061, Shaanxi, People’s Republic of China

    Yanting Zhu

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Zhang, Q., Li, W., Zhu, Y. et al. Activation of AMPK inhibits Galectin-3-induced pulmonary artery smooth muscle cells proliferation by upregulating hippo signaling effector YAP. Mol Cell Biochem 476, 3037–3049 (2021). https://doi.org/10.1007/s11010-021-04131-3

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