Activation of nuclear factor-?B pathway is responsible for tumor necrosis factor-a-induced up-regulation of endothelin B2 receptor expression in vascular smooth muscle cells in vitro.

Toxicology letters

PubMedID: 22207076

Zhang W, Li XJ, Zeng X, Shen DY, Liu CQ, Zhang HJ, Xu CB, Li XY. Activation of nuclear factor-?B pathway is responsible for tumor necrosis factor-a-induced up-regulation of endothelin B2 receptor expression in vascular smooth muscle cells in vitro. Toxicol Lett. 2012;209(2):107-12.
The endothelin B2 (ET(B2)) receptors are induced in vascular smooth muscle cells (VSMCs) in cardiovascular diseases. We tested if in vitro short-term exposure to the pro-inflammatory cytokine tumor necrosis factor-a (TNF-a) could up-regulate ET(B2) receptors in rat mesenteric arteries, and if this effect is through activation of intracellular nuclear factor-?B (NF-?B) pathway. The mesenteric arteries were dissected from male Sprague-Dawley rats and the endothelium was removed. The arteries were co-incubated with TNF-a in serum-free Dulbecco's modified Eagle's medium. Real-time reverse transcription-PCR, Western blot and immunohistochemical staining were employed to assess the mRNA/protein expression of ET(B2) receptors and activation of NF-?B pathway. The results showed that, during organ culture, TNF-a concentration-dependently enhanced ET(B2) receptors expression at both mRNA and protein levels, paralleled with activation of NF-?B pathway in VSMC. The up-regulated ET(B2) receptor expression and NF-?B activation could be effectively suppressed by general transcriptional inhibitor actinomycin D, or either of the selective I?B kinase inhibitors wedelolactone and IMD-0354. Conclusively, the activation of intracellular NF-?B pathway is responsible for the up-regulation of ET(B2) receptors induced by short-term exposure to TNF-a. This could partly explain the toxic effects of TNF-a on VSMCs that account for cardiovascular diseases.