Phosphatase activity in the arterial wall after balloon injury: Effect of somatostatin analog octreotide

Phosphorylation of transcription factors fos/jun dimer activator protein (A P)-1 and nuclear factor-kappaB (NF-kappa B) plays a cardinal role in vascul ar smooth muscle cell (SMC) response to growth stimuli. Activity of protein tyrosine (PTP) and serine/threonine phosphatases (PP2A, B, and C) regulate s in balance with the activity of protein kinases the level of transcriptio n factor phosphorylation. Somatostatin analog octreotide stimulates phospha tase activity and inhibits cell growth. We examined in rats the activity of tissue phosphatases after arterial wall injury and treatment with octreoti de and its effect: on AP-I and NF-kappa B phosphorylation and arterial resp onse to injury. The activity of PTP did not change after balloon injury. Tr eatment of rats with PTP stimulator octreotide increased the PTP activity b y 20% +/- 18% in uninjured arteries (p = 0.04 compared with control) and by 49% +/- 44% compared with injured untreated rats (p = 0.017). Treatment of rats with okadaic acid, a specific phosphatase inhibitor, prevented the oc treotide-induced increase in PTP activity. PP2A activity of uninjured arter ies was not affected significantly with treatment with octreotide (105% +/- . 21%, p = 0.57 compared with control). After balloon injury PP2A activity was significantly reduced, 54% +/- 24% of control (p = 0.001). This reducti on was prevented with treatment with octreotide, activity 88% +/- 25% of co ntrol. When rats were treated with octreotide and okadaic acid, the activit y of PP2A in uninjured arteries was decreased to 65% +/- 12% of control (p = 0.03) and the injury-induced reduction was preserved, activity 54% +/- 8% of control (p = 0.001). There was no change in PP2B and C activity after b alloon injury. Increased phosphatase activity with octreotide was associate d with stabilization of the unphosphorylated form and reduction in nuclear binding of AP-I and NF-kappa B and was associated with reduced SMC prolifer ation after balloon injury. Inhibition of increased phosphatase activity wi th okadaic acid was associated with increased nuclear binding of AP-I and N F-kappa B. increased nuclear binding of AP-I and NF-kappa B after injury wa s associated with increased expression of fos, jun, and p105 subunit mRNA a nd restored the proliferative response of SMC after balloon injury. We conc lude that the activity of PP2A is decreased after arterial balloon injury w hich leads to increased AP-I and NF-kappa B phosphorylation and nuclear bin ding and is involved in regulation of SMC proliferation. Treatment with oct reotide prevented the injury-induced reduction in PP2A activity and decreas ed transcription factor phosphorylation and SMC proliferation. Modification of phosphatase activity is a potential regulatory mechanism of arterial wa ll response to injury.