Sarco/endoplasmic reticulum Ca2+-ATPase gene transfer reduces vascular smooth muscle cell proliferation and neointima formation in the rat.
Proliferation of vascular smooth muscle cells (VSMC) is a primary cause of vascular disorders and is associated with major alterations in Ca2+ handling supported by loss of the sarco/endoplasmic reticulum calcium ATPase, SERCA2a. To determine the importance of SERCA2a in neointima formation, we have prevented loss of its expression by adenoviral gene transfer in a model of balloon injury of the rat carotid artery. Two weeks after injury, the intima/media ratio was significantly lower in SERCA2a-infected than in injured noninfected or injured beta-galactosidase-infected carotids (0.29+/-0.04 versus 0.89+/-0.19 and 0.72+/-0.14, respectively; P<0.05), and was comparable to that observed in control carotids (0.21+/-0.03). The pathways leading to proliferation were analyzed in serum-stimulated VSMC. Forced expression of SERCA2a arrested cell cycle at the G1 phase and prevented apoptosis. SERCA2a inhibits proliferation through inactivation of calcineurin (PP2B) and its target transcription factor NFAT (nuclear factor of activated T-cells) resulting in lowering of cyclin D1 and pRb levels. By using NFAT-competing peptide VIVIT, we showed that NFAT activity is strongly required to promote VSMC proliferation. In conclusion, we provide the first evidence that increasing SERCA2a activity inhibits VSMC proliferation and balloon injury-induced neointima formation.
Lipskaia
Larissa
L
INSERM U621/IFR-14, UPMC-CHU Pitié-Salpêtrière, Paris, France.
del Monte
Federica
F
Capiod
Thierry
T
Yacoubi
Sabrina
S
Hadri
Lahouaria
L
Hours
Michel
M
Hajjar
Roger J
RJ
Lompré
Anne-Marie
AM
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000502:physiology*; D002340:Carotid Artery Diseases / Q000517:prevention & control; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D022761:Gene Transfer, Horizontal; D015316:Genetic Therapy; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D014157:Transcription Factors / Q000378:metabolism; D017539:Tunica Intima / Q000473:pathology*
D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium