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

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 Ca(2+)-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 (?-galactosidase, ?-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 ?-gal-infected arteries). These findings could have potential implications for treatment of pathological in-stent restenosis.

SUBMITTER: Lipskaia L

PROVIDER: S-EPMC3465616 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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

Lipskaia L L Hadri L L Le Prince P P Esposito B B Atassi F F Liang L L Glorian M M Limon I I Lompre A-M AM Lehoux S S Hajjar R J RJ

Gene therapy 20120705 4

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 Ca(2+)-signaling pathways governing proliferation and migration. Moreover, SERCA2a gene transfer was reported to inhibit in vitro VSMC proliferation and to prevent neointimal t ...[more]

PMID: 22763406

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Project description:1. Explants of mammary gland from mid-pregnant rabbits were cultured in medium 199 containing insulin, prolactin and cortisol, and specific anti-casein immunoglobulin G was used to measure the amount, rate of synthesis and rate of degradation of casein in the explants in the presence of hormones and after removal of hormones from previously stimulated tissue. 2. The amount of casein in particle-free supernatants prepared from mammary explants was measured by ;rocket' immunoelectrophoresis. 3. The rate of incorporation of l-[4,5-(3)H]leucine into casein was measured after isolation of the casein by immunoadsorbent chromatography and polyacrylamide-gel electrophoresis in the presence of urea and sodium dodecyl sulphate. 4. Casein accumulates in mammary explants in the presence of insulin, prolactin and cortisol, but not in the absence of hormones. Removal of hormones after 24h in culture results in a decrease in the rate of accumulation of casein in the explants. 5. Casein-synthetic rate increases in mammary explants in the presence of insulin, prolactin and cortisol, but not in the absence of hormones. Removal of hormones after 24h in culture results in continued casein synthesis at approx. 30% of the rate in the presence of hormones. The synthetic rate does not decrease to values observed in explants cultured throughout in the absence of hormones. 6. Casein is not degraded in mammary explants during a phase of rapid casein accumulation (36-72h) in the presence of hormones. Furthermore casein is not degraded when hormones are removed from the tissue after between 36 and 72h in culture. 7. Casein is glycosylated in mammary explants; the extent of glycosylation parallels the rate of synthesis. The glycosylated protein is rapidly secreted from the tissue. 8. The results are consistent with the notion that after hormonal stimulation mammary explants from mid-pregnant rabbits synthesize, glycosylate and rapidly secrete casein. Removal of hormones decreases the synthetic rate of casein, but does not cause the accumulation of a pool of degradable casein in the lobuloalveolar cells.

Project description:BACKGROUND:Where each patient has all three conduits of internal mammary artery (IMA), saphenous vein graft (SVG) and radial artery (RA), most confounders affecting comparison between conduits can be mitigated. Additionally, since SVG progressively fails over time, restricting patient angiography to the late period only can mitigate against early SVG patency that may have occluded in the late period. METHODS:Research protocol driven conventional angiography was performed for patients with at least one of each conduit of IMA, RA and SVG and a minimum of 7 years postoperative. The primary analysis was perfect patency and secondary analysis was overall patency including angiographic evidence of conduit lumen irregularity from conduit atheroma. Multivariable generalized linear mixed model (GLMM) was used. Patency excluded occluded or "string sign" conduits. Perfect patency was present in patent grafts if there was no lumen irregularity. RESULTS:Fifty patients underwent coronary angiography at overall duration postoperative 13.1 ± 2.9, and age 74.3 ± 7.0 years. Of 196 anastomoses, IMA 62, RA 77 and SVG 57. Most IMA were to the left anterior descending territory and most RA and SVG were to the circumflex and right coronary territories. Perfect patency RA 92.2% was not different to IMA 96.8%, P = 0.309; and both were significantly better than SVG 17.5%, P < 0.001. Patency RA 93.5% was also not different to IMA 96.8%, P = 0.169, and both arterial conduits were significantly higher than SVG 82.5%, P = 0.029. Grafting according to coronary territory was not significant for perfect patency, P = 0.997 and patency P = 0.289. Coronary stenosis predicted perfect patency for RA only, P = 0.030 and for patency, RA, P = 0.007, and SVG, P = 0.032. When both arterial conduits were combined, perfect patency, P < 0.001, and patency, P = 0.017, were superior to SVG. CONCLUSIONS:All but one patent internal mammary artery or radial artery grafts had perfect patency and had superior perfect patency and overall patency compared to saphenous vein grafts.

Dataset Information

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

Publications

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

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