title: 8-chloro-cAMP inhibits smooth muscle cell proliferation in vitro and neointima formation induced by balloon injury in vivo.
abstract: OBJECTIVE
  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.
  
  
  BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular and Clinical Endocrinology and Oncology, University Federico II, Naples, Italy. Indolfi@unina.it
authors.forename: C
authors.initials: C
authors.lastname: Indolfi
authors.forename: E
authors.initials: E
authors.lastname: Di Lorenzo
authors.forename: A
authors.initials: A
authors.lastname: Rapacciuolo
authors.forename: A M
authors.initials: AM
authors.lastname: Stingone
authors.forename: E
authors.initials: E
authors.lastname: Stabile
authors.forename: A
authors.initials: A
authors.lastname: Leccia
authors.forename: D
authors.initials: D
authors.lastname: Torella
authors.forename: R
authors.initials: R
authors.lastname: Caputo
authors.forename: F
authors.initials: F
authors.lastname: Ciardiello
authors.forename: G
authors.initials: G
authors.lastname: Tortora
authors.forename: M
authors.initials: M
authors.lastname: Chiariello
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000293:injuries / Q000473:pathology; D001157:Arterial Occlusive Diseases / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control; D001794:Blood Pressure / Q000187:drug effects; D002404:Catheterization / Q000009:adverse effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007274:Injections, Intraperitoneal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D017539:Tunica Intima / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517836:Prkar1a protein, rat; C517839:Prkar2b protein, rat; D015124:8-Bromo Cyclic Adenosine Monophosphate; C044258:8-chloro-cyclic adenosine monophosphate; D017868:Cyclic AMP-Dependent Protein Kinases