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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 …