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SERCA2a gene transfer prevents intimal proliferation in an organ culture of human internal mammary artery

Gene Therapy volume 20, pages 396–406 (2013)Cite this article

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Abstract

Coronary restenosis, a major complication of percutaneous balloon angioplasty, results from neointimal proliferation of vascular smooth muscle cells (VSMCs). The sarco/endoplasmic reticulum calcium ATPase 2a isoform (SERCA2a), specific to contractile VSMCs, has been reported previously to be involved in the control of the Ca2+-signaling pathways governing proliferation and migration. Moreover, SERCA2a gene transfer was reported to inhibit in vitro VSMC proliferation and to prevent neointimal thickening in a rat carotid injury model. The aim of this study was to evaluate the potential therapeutic interest of SERCA2a gene transfer for prevention of in-stent restenosis using a ex vivo model of human left internal mammary artery (hIMA) intimal thickening. Left hIMAs, obtained at the time of aorto-coronary bypass surgeries, were subjected to balloon dilatation followed by infection for 30 min with adenoviruses encoding either human SERCA2 and green fluorescence protein (GFP) or control gene (β-galactosidase, β-gal) and GFP. Proliferation of subendothelial VSMCs and neointimal thickening were observed in balloon-injured hIMA maintained 14 days in organ culture under constant pressure and perfusion. SERCA2a gene transfer prevented vascular remodeling and significantly (P<0.01, n=5) reduced neointimal thickening in injured arteries (intima/media ratio was 0.07±0.01 vs 0.40±0.03 in β-gal-infected arteries). These findings could have potential implications for treatment of pathological in-stent restenosis.

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Acknowledgements

This work was supported by AHA SDG 0930116N (LL), by NIH (1K01HL103176) (LH), by Leducq Foundation through the Caerus network (05 CVD 03 to AML and RJH), by NIH R01 HL078691, HL057263, HL071763, HL080498 and HL083156 (RJH). We thank Dr A Tedgui (Paris Cardiovascular Research Center, HEGP, Paris, France) for helpful discussion; Drs S Kraner and CM Norris (Sanders-Brown Center on Aging, Lexington, KY, USA) for providing Ad-VIVIT, and Dr F Wuytack (University of Leuven, Belgium) for the anti-SERCA2a and anti-SERCA2b antibodies.

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Author notes

  1. S Lehoux and R J Hajjar: Authors share senior authorship.

Authors and Affiliations

  1. Transatlantic Cardiovascular Research Centre, Mount Sinai School of Medicine, New York, NY, USA

    L Lipskaia, L Hadri, L Liang & R J Hajjar

  2. Transatlantic Cardiovascular Research Centre, INSERM UMRS 956, Paris, France

    L Lipskaia, F Atassi & A-M Lompre

  3. Institut de Cardiologie, Hôpital Pitié–Salpêtrière, Paris, France

    P Le Prince

  4. Paris Cardiovascular Research Center, Inserm U970, HEGP, Paris, France

    B Esposito

  5. Transatlantic Cardiovascular Research Centre, Mount Sinai School of Medicine, University Paris 6, UR4, Paris, France

    M Glorian & I Limon

  6. Lady Davis Institute for Medical Research, McGill University, Montreal, Canada

    S Lehoux

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Lipskaia, L., Hadri, L., Le Prince, P. et al. SERCA2a gene transfer prevents intimal proliferation in an organ culture of human internal mammary artery. Gene Ther 20, 396–406 (2013). https://doi.org/10.1038/gt.2012.50

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