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Hydrogen sulfide upregulates KATP channel expression in vascular smooth muscle cells of spontaneously hypertensive rats

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A Correction to this article was published on 15 January 2021

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Abstract

The study was designed to investigate whether H2S could upregulate expression of KATP channels in vascular smooth muscle cells (VSMCs), and by this mechanism enhances vasorelaxation in spontaneously hypertensive rats (SHR). Blood pressure, vascular structure, and vasorelaxation were analyzed. Plasma H2S was detected using polarographic sensor. SUR2B and Kir6.1 expressions were detected in VSMCs of SHR and in A7r5 cells as well as primarily cultured ASMCs using real-time PCR, western blot, immunofluorescence, and confocal imaging. Nuclear translocation of forkhead transcription factors FOXO1 and FOXO3a in ASMCs was detected using laser confocal microscopy, and their binding activity with SUR2B and Kir6.1 promoters was examined by chromatin immunoprecipitation. SHR developed hypertension at 18 weeks. They showed downregulated vascular SUR2B and Kir6.1 expressions in association with a decreased plasma H2S level. H2S donor, however, could upregulate vascular SUR2B and Kir6.1 expressions, causing a left shift of the vasorelaxation curve to pinacidil and lowered tail artery pressure in the SHR. Also, H2S antagonized endothelin-1 (ET-1)-inhibited KATP expression in A7r5 cells and cultured ASMCs. Mechanistically, H2S inhibited ET-1-stimulated p-FOXO1 and p-FOXO3a expressions (inactivated forms), but increased their nuclear translocation and the ET-1-inhibited binding of FOXO1 and FOXO3a with Kir6.1 and SUR2B promoters in ASMCs. Hence, H2S promotes vasorelaxation of SHR, at least in part, through upregulating the expression of KATP subunits by inhibiting phosphorylation of FOXO1 and FOXO3a, and stimulating FOXO1 and FOXO3a nuclear translocation and their binding activity with SUR2B and Kir6.1 promoters.

Key messages

  • H2S increased vascular SUR2B and Kir6.1 expression of SHR, promoting vasorelaxation.

  • H2S antagonized ET-1-inhibited KATP expression in A7r5 cells and cultured ASMCs.

  • H2S inhibited ET-1-induced FOXO1 and FOXO3a phosphorylation in ASMCs.

  • H2S promoted FOXO1 and FOXO3a nuclear translocation and binding with target gene promoters.

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Acknowledgments

This work was supported by Major Basic Research Development Program of People's Republic of China (2012CB517806, 2013CB933801), National Natural Science Foundation of China (81100181 and 81121061), Beijing Natural Science Foundation (7121014, 7122184), Grant of Ministry of Education, China (20130001120047) and Program for New Century Excellent Talents of Ministry of Education, China (NCET-11-0005).

Conflict of interest

The authors have no financial conflict to declare.

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Authors and Affiliations

  1. Department of Pediatrics, Peking University First Hospital, Xi-An Men Street No. 1, West District, Beijing, 100034, China

    Yan Sun, Yaqian Huang, Rongyuan Zhang, Qinghua Chen, Yanfang Zong, Jia Liu, Shasha Feng, Die Liu, Junbao Du & Hongfang Jin

  2. Department of Pediatrics, Provincial School of Clinical Medicine, Fujian Medical University, Fuzhou, China

    Jie Chen

  3. Department of Medical and Health Sciences, Linköping University, Linköping, Sweden

    Angie Dong Liu & Lukas Holmberg

  4. Institute of Cardiovascular Diseases, Peking University First Hospital, Beijing, China

    Chaoshu Tang

  5. Key Laboratory of Molecular Cardiology, Ministry of Education, Beijing, China

    Chaoshu Tang & Junbao Du

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  1. Yan Sun
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Correspondence to Hongfang Jin.

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Yan Sun, Yaqian Huang, and Rongyuan Zhang contributed equally to this work

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Sun, Y., Huang, Y., Zhang, R. et al. Hydrogen sulfide upregulates KATP channel expression in vascular smooth muscle cells of spontaneously hypertensive rats. J Mol Med 93, 439–455 (2015). https://doi.org/10.1007/s00109-014-1227-1

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  • DOI: https://doi.org/10.1007/s00109-014-1227-1

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