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c-Fos expression in ouabain-treated vascular smooth muscle cells from rat aorta: evidence for an intracellular-sodium-mediated, calcium-independent mechanism

Sebastien Taurin, Nickolai O. Dulin*, Dimitri Pchejetski, Ryszard Grygorczyk, Johanne Tremblay, Pavel Hamet and Sergei N. Orlov

In this study, we examined the effect of Na⁺-K⁺ pump inhibition on the expression of early response genes in vascular smooth muscle cells (VSMC) as possible intermediates of the massive RNA synthesis and protection against apoptosis seen in ouabain-treated VSMC in our previous experiments. Incubation of VSMC with ouabain resulted in rapid induction of c-Fos protein expression with an approximately sixfold elevation after 2 h of incubation. c-Jun expression was increased by approximately fourfold after 12 h, whereas expression of activating transcription factor 2, cAMP/Ca²⁺ response element binding protein (CREB)-1 and c-Myc was not altered. Markedly augmented c-Fos expression was also observed under Na⁺-K⁺ pump inhibition in potassium-depleted medium. Na⁺-K⁺ pump inhibition triggered c-Fos expression via elevation of the [Na⁺]_i/[K⁺]_i ratio. This conclusion follows from experiments showing the lack of effect of ouabain on c-Fos expression in high-potassium-low-sodium medium and from the comparison of dose responses of Na⁺-K⁺ pump activity, [Na⁺]_i and [K⁺]_i content and c-Fos expression to ouabain. A fourfold increment of c-Fos mRNA was revealed 30 min following addition of ouabain to the incubation medium. At this time point, treatment with ouabain resulted in an approximately fourfold elevation of [Na⁺]_i but did not affect [K⁺]_i. Augmented c-Fos expression was also observed under VSMC depolarization in high-potassium medium. Increments in both c-Fos expression and ⁴⁵Ca uptake in depolarized VSMC were abolished under inhibition of L-type Ca²⁺ channels with 0.1 µM nicardipine. Ouabain did not affect the free [Ca²⁺]_i or the content of exchangeable [Ca²⁺]_i. Ouabain-induced c-Fos expression was also insensitive to the presence of nicardipine and [Ca²⁺]_o, as well as chelators of [Ca²⁺]_o (EGTA) and [Ca²⁺]_i (BAPTA). The effect of ouabain and serum on c-Fos expression was additive. In contrast to serum, however, ouabain failed to activate the Elk-1, serum response factor, CREB and activator protein-1 transcription factors identified within the c-Fos promoter. These results suggest that Na⁺-K⁺ pump inhibition triggers c-Fos expression via [Na⁺]_i-sensitive [Ca²⁺]_i-independent transcription factor(s) distinct from factors interacting with known response elements of this gene promoter.

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