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YAP-galectin-3 signaling mediates endothelial dysfunction in angiotensin II-induced hypertension in mice

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Abstract

Background

Vascular endothelial dysfunction is regarded as an early event of hypertension. Galectin-3 (Gal-3) is known to participate in various pathological processes. Whilst previous studies showed that inhibition of Gal-3 effectively ameliorates angiotensin II (Ang II)-induced atherosclerosis or hypertension, it remains unclear whether Ang II regulates Gal-3 expression and actions in vascular endothelium.

Methods

Using techniques of molecular biology and myograph, we investigated Ang II-mediated changes in Gal-3 expression and activity in thoracic aortas and mesenteric arteries from wild-type and Gal-3 gene deleted (Gal-3−/−) mice and cultured endothelial cells.

Results

The serum level of Gal-3 was significantly higher in hypertensive patients or in mice with chronic Ang II-infusion. Ang II infusion to wild-type mice enhanced Gal-3 expression in the aortic and mesenteric arteries, elevated systolic blood pressure and impaired endothelium-dependent relaxation of the thoracic aortas and mesenteric arteries, changes that were abolished in Gal-3−/− mice. In human umbilical vein endothelial cells, Ang II significantly upregulated Gal-3 expression by promoting nuclear localization of Yes-associated protein (YAP) and its interaction with transcription factor Tead1 with enhanced YAP/Tead1 binding to Gal-3 gene promoter region. Furthermore, Gal-3 deletion augmented the bioavailability of nitric oxide, suppressed oxidative stress, and alleviated inflammation in the thoracic aorta of Ang II-infused mice or endothelial cells exposed to Ang II.

Conclusions

Our results demonstrate for the first time that Ang II upregulates Gal-3 expression via increment in YAP nuclear localization in vascular endothelium, and that Gal-3 mediates endothelial dysfunction contributing to the development of hypertension.

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Data availability

Enquiries about data availability should be directed to the authors.

Abbreviations

Ang II:

Angiotensin II

DHFR:

Dihydrofolate reductase

eNOS:

Endothelial nitric oxide synthase

Gal-3:

Galectin-3

GPCRs:

G protein-coupled receptors

HUVECs:

Human umbilical vein endothelial cells

IL-6:

Interleukin-6

MAECs:

Mouse thoracic aorta endothelial cells

MCP-1:

Monocyte chemoattractant protein-1

NO:

Nitric oxide

NOX2:

Nicotinamide adenine dinucleotide phosphate oxidase 2

ROS:

Reactive oxygen species

Tead1:

TEA domain transcription factor 1

VCAM-1:

Vascular cell adhesion molecule-1

YAP:

Yes-associated protein

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Acknowledgements

None.

Funding

This work was supported by the National Natural Science Foundation of China (grant numbers 81870223 and 82170298), Natural Science Foundation of Shannxi province (grant number 2022JM-557). Yulin Science and Technology Project (grant number CXY-2020-048).

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Author notes

  1. Zheng-Da Pang and Xia Sun contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology and Pathophysiology, Cardiovascular Research Centre, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, 76 West Yanta Road, Xi’an, 710061, Shaanxi, China

    Zheng-Da Pang, Xia Sun, Ru-Yue Bai, Meng-Zhuan Han, Yong-Jian Zhang, Wei Wu, Yu Zhang, Bao-Chang Lai, Yi Zhang, Yan Wang, Xiao-Jun Du & Xiu-Ling Deng

  2. Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an Jiaotong University Health Science Center, 76 West Yanta Road, Xi’an, 710061, Shaanxi, China

    Zheng-Da Pang & Xiu-Ling Deng

  3. Department of Cardiac Surgery, The First Affiliated Hospital, Xi’an Jiaotong University, 277 West Yanta Road, Xi’an, 710061, Shaanxi, China

    Yong-Jian Zhang

  4. School of Basic and Medical Sciences, Xi’an Medical University, 1 Xinwang Road, Xi’an, 710021, Shaanxi, China

    Xia Sun

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  1. Zheng-Da Pang
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Contributions

ZDP, XS, XJD and XLD contributed to the study conception and design. Material preparation, data collection and analysis were performed by ZDP, XS, RYB, MZH, YJZ, WW, YZ, BCL, YIZ, YW, XJD and XLD. The first draft of the manuscript was written by ZDP, XJD and XLD. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xiao-Jun Du or Xiu-Ling Deng.

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The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

The animal study was approved by the Institutional Animal Care and Use Committee of Xi’an Jiaotong University and conformed to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health, USA. The human study was performed in accordance with the guidelines in the Declaration of Helsinki and was approved by the Ethics Committee of Xi’an Jiaotong University Health Science Center (No. 2020-607).

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Pang, ZD., Sun, X., Bai, RY. et al. YAP-galectin-3 signaling mediates endothelial dysfunction in angiotensin II-induced hypertension in mice. Cell. Mol. Life Sci. 80, 38 (2023). https://doi.org/10.1007/s00018-022-04623-5

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