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RECEPTORS AND SIGNAL TRANSDUCTION

Effects of the JNK inhibitor anthra[1,9-cd]pyrazol-6(2H)-one (SP-600125) on soluble guanylyl cyclase ₁ gene regulation and cGMP synthesis

¹Institute of Molecular Medicine, University of Texas–Houston Health Science Center; and ²Department of Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, Texas

Submitted 10 February 2005 ; accepted in final form 4 May 2005

The decreased expression of the nitric oxide (NO) receptor, soluble guanylyl cyclase (sGC), occurs in response to multiple stimuli in vivo and in cell culture and correlates with various disease states such as hypertension, inflammation, and neurodegenerative disorders. The ability to understand and modulate sGC expression and cGMP levels in any of these conditions could be a valuable therapeutic tool. We demonstrate herein that the c-Jun NH₂-terminal kinase JNK II inhibitor anthra[1,9-cd]pyrazol-6(2H)-one (SP-600125) completely blocked the decreased expression of sGC₁-subunit mRNA by nerve growth factor (NGF) in PC12 cells. Inhibitors of the ERK and p38 MAPK pathways, PD-98059 and SB-203580, had no effect. SP-600125 also inhibited the NGF-mediated decrease in the expression of sGC₁ protein as well as sGC activity in PC12 cells. Other experiments revealed that decreased sGC₁ mRNA expression through a cAMP-mediated pathway, using forskolin, was not blocked by SP-600125. We also demonstrate that TNF-/IL-1 stimulation of rat fetal lung (RFL-6) fibroblast cells resulted in sGC₁ mRNA inhibition, which was blocked by SP-600125. Expression of a constitutively active JNKK2-JNK1 fusion protein in RFL-6 cells caused endogenous sGC₁ mRNA levels to decrease, while a constitutively active ERK2 protein had no effect. Collectively, these data demonstrate that SP-600125 may influence the intracellular levels of the sGC₁-subunit in certain cell types and may implicate a role for c-Jun kinase in the regulation of sGC₁ expression.

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