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Down-Regulation of Soluble Guanylyl Cyclase Expression by Cyclic AMP Is Mediated by mRNA-Stabilizing Protein HuR

Institut für Kardiovaskuläre Physiologie, Johann Wolfgang v. Goethe-Universität, Frankfurt/Main, Germany

We analyzed whether the cyclic AMP induced down-regulation of the nitric oxide (NO) receptor soluble guanylyl cyclase (sGC) is mediated by the mRNA-protecting protein HuR. Exposure (up to 24 h) of isolated rat aortic segments to the activator of adenylyl cyclase, forskolin (10 µM), and to both activators of cAMP-stimulated protein kinase (PKA), 5,6-dichloro-1--D-ribofuranosylbenzimidazole-3',5'-cyclic monophosphorothioate, Spisomer (Sp-5,6-DCl-cBIMPS; 400 nM), and N⁶-phenyl-cAMP (10 µM), strongly reduced sGC₁₁ and HuR protein and mRNA expression in a time-dependent and actinomycin D (10 µM)-sensitive fashion. In vitro degradation of sGC₁ and ₁ poly(A)⁺ mRNA by native rat aortic protein was markedly increased by pretreatment of intact aortas with forskolin. Native protein extract from rat aorta shifted the electrophoretic mobility of biotin-labeled riboprobes from the 3'-untranslated region of sGC₁ and ₁ mRNA, and these bands was supershifted by a monoclonal antibody directed against the mRNA-stabilizing protein HuR. Forskolin decreased the HuR-sGC₁ and ₁ mRNA interaction and HuR protein expression in rat aorta, and this was prevented by the PKA inhibitory cAMP analog 3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS). In cultured smooth muscle cells from rat aorta, forskolin induced a rapid increase in Fos/p-Fos protein levels and activator protein 1 (AP-1) binding activity. Inhibition of this transcription factor by an AP-1 decoy prevented the forskolin-induced down-regulation of HuR. We conclude that forskolin/cAMP decrease the expression of heterodimeric sGC in rat aortic smooth muscle cells via activation of Fos/AP-1, which decreases the expression of HuR and thus destabilizes the sGC₁ and ₁ mRNA.

Address correspondence to: Stephan Kloess, Institut für Kardiovaskuläre Physiologie, Universität Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt. E-mail: s.kloess{at}em.uni-frankfurt.de

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