Indolfi, C, DI LORENZO, E, Rapacciuolo, A, Stingone, Am, Stabile, E, Leccia, A, Torella, D, Caputo, R, Ciardiello, Fortunato, Tortora, G, Chiariello, M., Rapacciuolo, Antonio, Stabile, Eugenio, Ciardiello, F, Chiariello, Massimo, Stingone, A. M., Tortora, Giampaolo
المصدر:
Journal of the American College of Cardiology. (1):288-293
بيانات النشر:
American College of Cardiology. Published by Elsevier Inc.
OBJECTIVESThe aims of the present study were to assess 1) the effect of 8-Cl-cAMP (cyclic-3′-5′-adenosine monophosphate) on vascular smooth muscle cell (VSMC) proliferation in vitro and 2) the efficacy of systemic administration of 8-Cl-cAMP on neointimal formation after balloon injury in vivo.BACKGROUNDNeointimal formation after vascular injury is responsible for restenosis after arterial stenting. Recently, 8-Cl-cAMP, a cAMP analogue that induces growth arrest, has been safely administered in phase I studies in humans.METHODSThe effect of 8-Cl-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.RESULTSThe 8-Cl-cAMP markedly inhibited VSMC proliferation in vitro, reduced protein kinase A (PKA) RIα subunit expression, and induced PKA RIIβ subunit expression. In addition, 8-Cl-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-Cl-cAMP group. Moreover, the systemic administration of 8-Cl-cAMP did not affect renal function, blood pressure and heart rate.CONCLUSIONSWe conclude that 8-Cl-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.
