Stabile D-peptide analog of insulin-like growth factor-1 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 significant elevation of IGF-1, platelet-derived growth factor B, transforming growth factor beta 1, and epidermal growth factor mRNAs 10 days after endothelial injury, concomitantly with the induction of intimal SMC proliferation and intimal thickening. Administration of 10-30 micrograms.kg-1.day-1 of D-analog of IGF-1, devoid of proteolytic degradation in body fluids, reduced intimal 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-1 at the level of IGF-1R may offer an entirely new approach for the prophylaxis and treatment of restenosis after cardiac revascularization procedures.
Häyry
P
P
Transplantation Laboratory, University of Helsinki, Finland.
Myllärniemi
M
M
Aavik
E
E
Alatalo
S
S
Aho
P
P
Yilmaz
S
S
Räisänen-Sokolowski
A
A
Cozzone
G
G
Jameson
B A
BA
Baserga
R
R
D000595:Amino Acid Sequence; D017130:Angioplasty / Q000009:adverse effects*; D000818:Animals; D001483:Base Sequence; D002339:Carotid Arteries / Q000166:cytology; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D004730:Endothelium, Vascular / Q000166:cytology; D015870:Gene Expression; D006131:Growth Inhibitors / Q000494:pharmacology; D006133:Growth Substances / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D011920:Rats, Inbred WF; D017539:Tunica Intima / Q000166:cytology
D017931:DNA Primers; D006131:Growth Inhibitors; D006133:Growth Substances; D010446:Peptide Fragments; C096150:insulin-like growth factor-1 D peptide; D007334:Insulin-Like Growth Factor I; D011505:Protein-Tyrosine Kinases