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

This work was presented in part at the 47th Annual Scientific Session of the American College of Cardiology, Atlanta, Georgia, March 1998. The authors did not receive any financial support.
https://doi.org/10.1016/S0735-1097(00)00679-3Get rights and content
Under an Elsevier user license
open archive

Abstract

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) 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.

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

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

Cited by (0)