1116. Gene Transfert of SERCA2a Inhibits Smooth Muscle Proliferation and Reduce Neointima Formation after Balloon Injury in the Rat

Abstract

Proliferation of vascular smooth muscle cells (VSMC) is associated with major alterations in SR Ca2+ handling and loss of SERCA 2a. We have restored SERCA 2a expression by adenoviral gene transfer in a model of neointima formation induced by balloon injury of the left carotid artery of the rat using a 2F Fogarty catheter. The effect of gene delivery was evaluated after 2 weeks with morphometry and immunohistochemical staining. There was no significant difference in the thickness of the media between groups. The intima/media ratio was significantly lower in SERCA 2a infected than in injured non-infected (0.29 |[plusmn]| 0.043, n=5 vs 0.85 |[plusmn]| 0.179, n=5 p< 0.05) carotids, and was comparable to that observed in control carotids (0.196 |[plusmn]| 0.025, n=11, NS). The SERCA 2a-infected carotids displayed a differentiated phenotype. The pathways leading to inhibition of proliferation was analysed in rat aortic VSMC cultured in presence of serum. Forced expression of SERCA 2a was sufficient to arrest proliferation at the G1 phase. SERCA 2a expression resulted in inactivation of calcineurin. The transcriptional activity of its target, NFAT was greatly reduced in SERCA 2a-expressing cells. Furthermore, SERCA 2a increased pCREB transcriptional activity and expression of its target p21Waf1/Cip1 without any changes in p27 KIP.