Inhibitory mechanisms by which suramin may attenuate neointimal formation after balloon angioplasty.
Restenotic neointimal lesions, a major limitation to coronary angioplasty, develop in response to diverse signals and depend on three properties of activated arterial smooth muscle cells (SMCs): proliferation, migration, and abnormal production of extracellular matrix. Most of the pharmacologic approaches targeting specific pathogenic factors facilitating development of restenosis have failed in clinical trials. Our results indicate that the polysulfonated naphthylurea suramin, a "non-specific drug" that interferes with multiple cellular proteins, inhibits neointimal formation in rabbit iliac arteries after balloon-catheter injury administered throughout the critical period of several weeks after the procedure. In vitro studies aimed at dissecting the mechanism(s) underlying the suramin-dependent effect demonstrated that, in addition to an inhibitory effect on SMC proliferation, suramin inhibited fibronectin and elastin deposition and the migration of SMCs through elastin membranes and into scratch gaps of monolayer cultures. We also demonstrated that suramin causes cell-surface accumulation of the elastin binding protein, a receptor that not only anchors SMCs to the extracellular matrix, but also inhibits SMC response to interleukin-1beta (IL-1beta). We conclude that suramin acts as a multitarget inhibitor of SMC activation and has a therapeutic potential as an agent that may attenuate arterial restenosis after angioplasty.
Gray
T J
TJ
The Hospital for Sick Children, Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.
Strauss
B H
BH
Hinek
A
A
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018929:Cell Culture Techniques; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D003327:Coronary Disease / Q000628:therapy*; D004247:DNA / Q000096:biosynthesis; D004549:Elastin / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D007083:Iliac Artery / Q000187:drug effects / Q000293:injuries / Q000502:physiology; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D009710:Nucleotide Mapping; D011485:Protein Binding; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000502:physiology; D013498:Suramin / Q000494:pharmacology*; D017539:Tunica Intima / Q000187:drug effects* / Q000293:injuries
D000970:Antineoplastic Agents; D005353:Fibronectins; D007375:Interleukin-1; D011956:Receptors, Cell Surface; C054901:elastin-binding proteins; D013498:Suramin; D004247:DNA; D004549:Elastin