Objective-Arginase stimulates the proliferation of cultured vascular smooth muscle cells (VSMCs); however, the influence of arginase on VSMC growth in vivo is not known. This study investigated the impact of arginase on cell cycle progression and neointima formation after experimental arterial injury. Methods and Results-Balloon injury of rat carotid arteries resulted in a sustained increase in arginase activity in the vessel wall and the induction of arginase I protein in both the media and neointima of injured vessels. Furthermore, local perivascular application of the potent and selective arginase inhibitors

Objective-Mitomycin C (MMc) is an antibiotic that exerts a potent antiproliferative effect in tumor cells. Because the proliferation of vascular smooth muscle cells (VSMCs) plays a prominent role in the development of restenosis after percutaneous coronary interventions, the present study examined the effect of MMc on VSMC proliferation and on neointima formation after arterial balloon injury. Methods and Results-Treatment of cultured rat aortic VSMCs with MMc (1 nmol to 30 mol/L) inhibited VSMC proliferation in a concentration-dependent manner. Whereas high concentrations of MMc (1 to 30 mol/L) induced VSMC apoptosis, as reflected by DNA laddering and caspase-3 activation, lower concentrations of MMc (1 to 300 nmol/L) directly inhibited VSMC growth by arresting cells in the G 2 /M phase of the cell cycle. The antiproliferative action of MMc was associated with a selective increase in the expression of the cyclin-dependent kinase inhibitor p21, and with a decrease in cyclin B1-cyclin-dependent kinase-1 complex activity. Finally, the local perivascular delivery of MMc immediately after balloon injury of rat carotid arteries induced p21 expression and markedly attenuated neointima formation. Key Words: angioplasty Ⅲ arteries Ⅲ mitomycin C Ⅲ restenosis Ⅲ smooth muscle cells T he healing response to stent implantation starts immediately after injury, generally peaks at 2 weeks after the initial insult has occurred, and is mainly regulated by vascular smooth muscle cells (VSMCs). 1-3 Drug-eluting stents reduce restenosis by decreasing the formation of a neointima caused by excessive cellular activation after arterial injury. 4,5 The successful development of drug-eluting stents has relied on the controlled release of antiproliferative agents over several weeks to regulate the activation and proliferation of VSMCs. 4,5 Accordingly, potent antiproliferative agents have the potential of decreasing the degree of neointimal formation after stent implantation if cytostatic rather than cytotoxic tissue levels can be achieved at the site of injury. Conclusion-TheseMitomycin C (MMc) is an antibiotic agent with antiproliferative properties derived from the soil fungus Streptomyces caespitosus. 6 In addition to cancer therapy, 7 MMc is a well-recognized antifibroblastic drug. In vitro studies using cultured human fibroblasts have shown that after exposure to a single dose of MMc, there is a profound inhibition of the proliferative phase of the wound-healing response, specifically through the inhibition of fibroblast replication. 8 These findings have led to the successful clinical use of MMc as an adjuvant in procedures displaying excessive late-onset scar tissue formation, 8 -10 and suggest that MMc may be suitable as an agent to decrease neointima formation. Accordingly, we sought to evaluate the growth modulating potential of MMc on cultured rat arterial VSMCs and the impact of MMc on neointima formation in a rat model of arterial balloon injury. Methods MaterialsMMc was purchased from Henan Kangtai Pharmaceutical Group (Zh...

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