Endothelin-1 induces hypoxia inducible factor 1 alpha expression in pulmonary artery smooth muscle cells
- 医学院－已发表论文 
Endothelin-1 (ET-1) dose-dependently increased HIF1 alpha expression in pulmonary artery smooth muscle cells (PASMCs). Inhibition of protein synthesis did not affect ET-1-induced HIF1 alpha expression. The maximum effect of ET-1 was similar to that caused by proteasome inhibitor MG132. Further study indicates that ET-1 also dose-dependently stimulated calcineurin activation, specific calcineurin inhibitor cyclosporine A (CsA), abolished ET-1-induced HIF1 alpha elevation, and reversed ET-1-induced RACK1 (receptor of activated protein kinase C 1) de-phosphorylation. Endothelin receptor A was found to specifically mediate the effects of ET-1. To examine whether RACK1 is particularly involved in proteasome-dependent HIF1 alpha degradation, RACK1 was silenced by siRNA transfection. Cells lacking RACK1 exhibited significant elevation of HIF1 alpha protein level. Taken together, our study suggests that ET-1 suppressed proteasome-dependent HIF1 alpha degradation by calcineurin-dependent RACK1 de-phosphorylation. (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.