Stabile D‐peptide analog of insulin‐like growth factor‐l inhibits smooth muscle cell proliferation after carotid ballooning injury in the rat

Restenosis after angioplasty is believed to result from stimulation of smooth muscle cells (SMC) by various growth-promoting factors as a consequence of endothelial injury. In this study we have tested the hypothesis that insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) interaction is a rate-limiting step for SMC replication by blocking this interaction with a synthetic D-amino acid peptide structurally resembling the D-domain of IGF-1. After rat carotid artery denudation, semiquantitative PCR analysis demonstrated a sig-nificant elevation of IGF-1, platelet-derived growth factor B, transforming growth factor βl, and epider-mal growth factor mRNAs 10 days after endothelial injury, concomitantly with the induction of intimai SMC proliferation and intimai thickening. Admini-stration of 10-30 μg·kg-l·day-l of D-analog of IGF-1, devoid of proteolytic degradation in body fluids, reduced intimai SMC replication by 60-70%. The peptide also inhibited [3H]TdR incorporation and [3H]glycine incorporation in cultured SMCs by 60-80%, whereas a "scrambled" control peptide consisting of the same amino acids had no effect. The results suggest that IGF- 1/IGF- 1R interaction is a rate-limiting step for SMC replication. Blocking of this interaction with stabile D-peptide analog of IGF-l at the level of IGF-1R may offer an entirely new approach for the prophylaxis and treatment of reetenoeis after cardiac revascularization procedures.—Häyry, P., Myllärniemi, M., Einari, A., Alatalo, S., Aho, P., Yilmaz, S., Räisänen-Sokolowski, A., Cozzone, G., Jameson, B. A., Baserga, R. Stable D-peptide analog of insulin-like growth factor-1 inhibits smooth muscle cell proliferation after carotid ballooning injury in the rat. FASEB J. 9, 1336-1344 (1995)