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Endothelin‐1 induces hypoxia inducible factor 1α expression in pulmonary artery smooth muscle cells
Author(s) -
Li Manxiang,
Liu Yuan,
Jin Faguang,
Sun Xiuzhen,
Li Zongfang,
Liu Yun,
Fang Ping,
Shi Hongyang,
Jiang Xingtang
Publication year - 2012
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2012.08.036
Subject(s) - mg132 , calcineurin , endothelin 1 , proteasome inhibitor , protein kinase c , phosphorylation , proteasome , microbiology and biotechnology , endothelin receptor , chemistry , receptor , biology , endocrinology , medicine , transplantation , biochemistry
Endothelin‐1 (ET‐1) dose‐dependently increased HIF1α expression in pulmonary artery smooth muscle cells (PASMCs). Inhibition of protein synthesis did not affect ET‐1‐induced HIF1α 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 HIF1α 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 HIF1α degradation, RACK1 was silenced by siRNA transfection. Cells lacking RACK1 exhibited significant elevation of HIF1α protein level. Taken together, our study suggests that ET‐1 suppressed proteasome‐dependent HIF1α degradation by calcineurin‐dependent RACK1 de‐phosphorylation.