Inhibitors of the MAPK/ NF-κB pathway attenuate the upregulation of the ETB receptor mediated by high glucose in vascular smooth muscle cells

Xia Sun; Hongmei Zhang; Qiaohong Qin; Xin Zhang; Ying Hou; Di Chen; Xingli Su; Min Jia; Yulong Chen

doi:10.1016/j.peptides.2021.170732

Inhibitors of the MAPK/ NF-κB pathway attenuate the upregulation of the ET_B receptor mediated by high glucose in vascular smooth muscle cells

Peptides. 2022 Apr:150:170732. doi: 10.1016/j.peptides.2021.170732. Epub 2021 Dec 29.

Authors

Xia Sun¹, Hongmei Zhang², Qiaohong Qin³, Xin Zhang³, Ying Hou³, Di Chen¹, Xingli Su¹, Min Jia⁴, Yulong Chen⁵

Affiliations

¹ Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, 710021, China; School of Basic and Medical Sciences, Xi'an Medical University, Xi'an, Shaanxi, 710021, China.
² The First Affiliated Hospital of Xi'an Medical University, Xi'an Medical University, Xi'an, Shaanxi, 710077, China.
³ Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, 710021, China.
⁴ Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, 710021, China. Electronic address: jiamin_jzs@xiyi.edu.cn.
⁵ Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi, 710021, China. Electronic address: chenyulong_jzs@xiyi.edu.cn.

PMID: 34971676
DOI: 10.1016/j.peptides.2021.170732

Abstract

Background: Increased vascular smooth muscle cell (VSMC) endothelin type B (ET_B) receptor expression is involved in cardiovascular diseases. High glucose (HG) in diabetes is closely related to cardiovascular complications. Although diabetes upregulates VSMC endothelin subtype B (ET_B) receptors, its mechanism is still unclear. Our aim is to investigate the mechanism of HG-induced ET_B receptors in VSMCs.

Methods: Rat superior mesenteric arteries (SMAs) without endothelium were cultured in medium without serum for 24 h. HG with or without mitogen-activated protein kinase (MAPK) signaling pathway inhibitors and downstream nuclear factor-kappaB (NF-κB) inhibitors was coincubated with SMAs. A sensitive myograph detected the contractile responses to sarafotoxin 6c. Western blotting and immunofluorescence staining were used to determine protein expression.

Results: HG promoted the expression of VSMC ET_B receptors in rat SMAs and enhanced the ET_B receptor-induced contractile response. The results showed that HG increased vascular smooth muscle cell (VSMC) ET_B receptor expression and ET_B receptor-induced contractile responses in rat SMAs. Both extracellular signal-related kinase 1 and 2 (ERK1/2) inhibitors (U0126) and P38 inhibitors (SB203580) significantly inhibited HG-increased VSMC ET_B receptors. However, a C-jun terminal kinase (p-JNK) inhibitor (SP600125) did not affect HG- upregulated VSMC ET_B receptors. Further study showed that NF-κB using an IκB kinase inhibitor (wedelolactone) also significantly inhibited HG-increased VSMC ET_B receptors.

Conclusion: In conclusion, HG upregulated the VSMC ET_B receptor by activating the ERK1/2- or P38- NF-κB signaling pathway.

Keywords: Blood glucose; Endothelin receptors; MAPK.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Glucose / metabolism
Mitogen-Activated Protein Kinases / genetics
Mitogen-Activated Protein Kinases / metabolism
Muscle, Smooth, Vascular* / metabolism
NF-kappa B* / metabolism
Protein Kinase Inhibitors
Rats
Receptor, Endothelin B / genetics
Up-Regulation
Vasoconstriction

Substances

NF-kappa B
Protein Kinase Inhibitors
Receptor, Endothelin B
Mitogen-Activated Protein Kinases
Glucose