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Glucose-regulated protein 78 in lipid rafts elevates vascular smooth muscle cell proliferation of spontaneously hypertensive rats by controlling platelet-derived growth factor receptor signaling

  • Signaling and cell physiology
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Abstract

The multifunctional glucose-regulated protein 78 (GRP78) is known to be differentially expressed in the lipid rafts of vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHRs) and normal Wistar-Kyoto (WKY) rats. However, its role in VSMCs from SHRs remains to be elucidated. This work was conducted to investigate the contribution made by GRP78 in VSMCs. GRP78 expression in VSMC lipid rafts decreased in WKY rats with age, but not in SHRs. Transfection with GRP78-siRNA attenuated not only platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation and aortic sprout outgrowth but also the phosphorylation of PDGF receptor (PDGFR)-β, Akt, and extracellular signal-regulated kinase (Erk) 1/2 in VSMCs in response to PDGF-BB. Moreover, GRP78 knockdown also reduced the PDGF-BB-induced dimerization of PDGFR-β and GRP78 in SHR VSMCs. The phosphorylation of GRP78 and PDGFR-β was elevated in VSMCs treated with PDGF-BB and was completely abolished by AG1296 (a PDGFR inhibitor). Moreover, the binding of PDGFR-β to GRP78 and the co-localization of GRP78 to PDGFR-β in VSMCs were stronger in SHRs than in WKY rat controls. This study demonstrates that the PDGF-BB-induced proliferation of SHR VSMCs is mediated by the expressional upregulation of GRP78 on VSMC lipid rafts in SHRs, probably via the regulation of PDGFR-β-GRP78 binding and their cross-activation. These observations indicate that GRP78 may play important roles in the pathological progression of SHR VSMCs.

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Funding

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (2010-0004566) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C1540).

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Authors and Affiliations

  1. Department of Cosmetic Science, College of Life and Health, Hoseo University, 79 Hoseo-ro, Asan, 31499, South Korea

    Do-Yoon Kim, Dae Il Hwang, Soo Min Park & Hwan Myung Lee

  2. College of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang, 414006, Hunan, China

    Do-Yoon Kim

  3. Department of Physiology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, South Korea

    Seung Hyo Jung, Bokyung Kim & Kyung Jong Won

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  1. Do-Yoon Kim
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Contributions

D.Y.K., K.J.W., and H.M.L. conceived and designed this research; D.Y.K., D.I.H., S.M.P., and S.H.J. performed acquisition of data; D.Y.K., D.I.H., and H.M.L. analyzed data; D.Y.K., B.K., K.J.W., and H.M.L. interpreted data; D.Y.K., B.K., K.J.W., and H.M.L. drafted manuscript; D.Y.K., D.I.H., S.M.P., J.S.H., K.J.W., and H.M.L. prepared figures. All authors approved final version of manuscript.

Corresponding authors

Correspondence to Kyung Jong Won or Hwan Myung Lee.

Ethics declarations

All animal procedures in this study were in strict adherence to the Guide for the Care and Use of Laboratory Animals as adopted by the U.S. National Institutes of Health (NIH publication No. 85-23, revised 2011) and were approved by the Animal Subjects Committee and by the Institutional Guidelines of Konkuk University, Korea.

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The authors declare that they have no conflict of interest.

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Kim, DY., Hwang, D.I., Park, S.M. et al. Glucose-regulated protein 78 in lipid rafts elevates vascular smooth muscle cell proliferation of spontaneously hypertensive rats by controlling platelet-derived growth factor receptor signaling. Pflugers Arch - Eur J Physiol 470, 1831–1843 (2018). https://doi.org/10.1007/s00424-018-2199-8

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  • DOI: https://doi.org/10.1007/s00424-018-2199-8

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