Cyclosporin A up-regulated thromboxane A2 receptor through activation of MAPK and NF-?B pathways in rat mesenteric artery

Cyclosporin A (CsA) is an immunosuppressant used in transplantation patients and inflammatory diseases. CsAinduced local vasoconstriction can lead to serious side effects including nephrotoxicity and hypertension. However, the underlying mechanisms are not fully understood. Mesenteric artery rings of rats were cultured with CsA and specific inhibitors for mitogen-activating protein kinases (MAPK) and nuclear factor-kappa B (NF-kappa B) signaling pathways. A sensitive myograph recorded thromboxane (TP) receptor-mediated vasoconstriction. Protein levels of key signaling molecules were assessed by Western blotting. The results show that CsA up-regulated the TP receptor expression with the enhanced vasoconstriction in a dose- and time-dependent manner. Furthermore, the blockage of MAPKs or NF-kappa B activation markedly attenuated CsA-enhanced vasoconstriction and the TP receptor protein expression. Rats subcutaneously injected with CsA for three weeks showed increased blood pressure in vivo and increased contractile responses to a TP agonist ex vivo. CsA also enhanced TP receptor, as well as p-ERK1/2, p-p38, p- I kappa B alpha, p-NF-kappa B P65 protein levels and decreased I kappa B alpha protein expression, demonstrating that CsA induced TP receptor enhanced-vasoconstriction via activation of MAPK and NF-kappa B pathways. In conclusion, CsA up-regulated the expression of TP receptors via activation of MAPK and NF-kappa B pathways. The results may provide novel options for prevention of CsA-associated hypertension.