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-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 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-κB using an IκB 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-κB signaling pathway.