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EXPERIMENTAL STUDIES

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

^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 RII_ß 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.

Abbreviations and Acronyms   ANOVA = analysis of variance   cAMP = cyclic-3'-5'-adenosine monophosphate   DMEM = Dulbecco’s modified Eagle’s medium   EEL = external elastic membrane   FCS = fetal calf serum   IEL = internal elastic membrane   PCNA = proliferating cell nuclear antigen   PKA = protein kinase A   PTCA = percutaneous transluminal coronary angioplasty   VSMCs = vascular smooth muscle cells

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