Endothelin-1 induces hypoxia inducible factor 1¦Á expression in pulmonary artery smooth muscle cells

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• 作者：Manxiang Li^a ; ^{manxiangli@hotmail.com} ; Yuan Liu^a ; Faguang Jin^b ; Xiuzhen Sun^a ; Zongfang Li^c ; Yun Liu^a ; Ping Fang^a ; Hongyang Shi^a ; Xingtang Jiang^d
• 关键词：Endothelin-1 ; HIF1¦Á ; Proteasome ; Calcineurin ; RACK1
• 刊名：FEBS Letters
• 出版年：2012
• 出版时间：2 November, 2012
• 年：2012
• 卷：586
• 期：21
• 页码：3888-3893
• 全文大小：383 K

文摘

Endothelin-1 (ET-1) dose-dependently increased HIF1¦Á expression in pulmonary artery smooth muscle cells (PASMCs). Inhibition of protein synthesis did not affect ET-1-induced HIF1¦Á 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¦Á 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¦Á degradation, RACK1 was silenced by siRNA transfection. Cells lacking RACK1 exhibited significant elevation of HIF1¦Á protein level. Taken together, our study suggests that ET-1 suppressed proteasome-dependent HIF1¦Á degradation by calcineurin-dependent RACK1 de-phosphorylation.