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J Am Coll Cardiol, 2000; 36:288-293 © 2000 by the American College of Cardiology Foundation |
a Laboratory of Experimental and Clinical Interventional Cardiology, University Federico II, Naples, Italy
* Department of Molecular and Clinical Endocrinology and Oncology, University Federico II, Naples, Italy
Manuscript received January 28, 1999; revised manuscript received January 17, 2000, accepted March 2, 2000.
Reprint requests and correspondence: Dr. Ciro Indolfi, Division of Cardiology, University Federico II, Via Pansini, 5, 80131 Napoli, Italy
Indolfi{at}unina.it
OBJECTIVES
The 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.
BACKGROUND
Neointimal 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.
METHODS
The 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.
RESULTS
The 8-Cl-cAMP markedly inhibited VSMC proliferation in vitro, reduced protein kinase A (PKA) RI
subunit expression, and induced PKA RIIß 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.
CONCLUSIONS
We 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.
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