Endothelin-1 (ET-1) induces prolonged AP-1 transcription factor DNA binding activity in vascular smooth muscle cells (VSMC) isolated from aged fischer 344 rats

The product of the fos and jun oncogenes, called AP-1 had been associated with enhanced cell proliferation. Also, ET-1, a potent vasoactive peptide had been shown to induce VSMC proliferation. In order to understand age-associated enhanced VSMC proliferation, we studied primary culture of VSMCs isolated from aortae of Fiscer 344 rats. Confluent, quiescent VSMCs isolated from 6 month (young VSMCs) and from 24 month (old VSMCs) old rats, passage 4 to 6, were treated with ET-1 (10^-7M) for various time intervals. Nuclear extracts were then collected and tested by gel shift assays. ET-1 induced AP-1 DNA binding activity in young VSMCs within 30 to 60 minutes, an effect that faded away at 2 hours. In contrast, ET-1 induction of AP-1 binding activity in the old cells persisted up to 4 hours. Our findings suggest that cells isolated from aged VSMCs may have an enhanced responsiveness to the vasoactive agonist ET-1 leading to prolonged AP-1 DNA binding activity. Whether this effect is secondary to decreased degradation of the transcription factor or prolonged expression of the corresponding oncogenes remains to be elucidated. These data may explain in part age-associated increased VSMC proliferation.