Inhibitors of the MAPK/ NF-κB Pathway Attenuate the Upregulation of the ETB Receptor Mediated by High Glucose in Vascular Smooth Muscle Cells.

Background: Increased vascular smooth muscle cell (VSMC) endothelin type B (ETB) 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 (ETB) receptors, its mechanism is still unclear. Our aim is to investigate the mechanism of HG-induced ETB 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-kappa B) 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 ETB receptors in rat SMAs and enhanced the ETB receptor-induced contractile response. The results showed that HG increased vascular smooth muscle cell (VSMC) ETB receptor expression and ETB 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 ETB receptors. However, a C-jun terminal kinase (p-JNK) inhibitor (SP600125) did not affect HG- upregulated VSMC ETB receptors. Further study showed that NF-kappa B using an I kappa B kinase inhibitor (wedelolactone) also significantly inhibited HG-increased VSMC ETB receptors. Conclusion: In conclusion, HG upregulated the VSMC ETB receptor by activating the ERK1/2-or P38-NF-kappa B signaling pathway.