8-chloro-cAMP inhibits smooth muscle cell proliferation in vitro and neointima formation induced by balloon injury in vivo.

Abstract

The aims of the present study were to assess 1) the effect of 8-C1-cAMP (cyclic-3'-5'-adenosine monophosphate) on vascular smooth muscle cell (VSMC) proliferation in vitro and 2) the efficacy of systemic administration of 8-C1-cAMP on neointimal formation after balloon injury in vivo. Neointimal formation after vascular injury is responsible for restenosis after arterial stenting. Recently, 8-C1-cAMP, a cAMP analogue that induces growth arrest, has been safely administered in phase I studies in humans. The effect of 8-C1-cAMP on cell proliferation was first assessed on SMCs in vitro. To study the effects of cAMP in vivo, balloon injury was performed in 67 rats using a 2F Fogarty balloon catheter. The 8-C1-cAMP markedly inhibited VSMC proliferation in vitro, reduced protein kinase A (PKA) RIalpha subunit expression, and induced PKA RIIbeta subunit expression. In addition, 8-C1-cAMP reduced, in a dose-dependent manner, neointimal area and neointima/media ratio after balloon injury. The proliferative activity, assessed by proliferating nuclear cell antigen immunostaining, revealed a reduction of proliferative activity of VSMCs in vivo in the 8-C1-cAMP group. Moreover, the systemic administration of 8-C1-cAMP did not affect renal function, blood pressure and heart rate. We conclude that 8-C1-cAMP potently inhibits VSMC proliferation in vitro and reduces neointima formation by balloon injury in vivo after systemic administration. These data may have a clinical relevance in designing future strategies to prevent restenosis after arterial stenting and perhaps after percutaneous transluminal coronary angioplasty.