A - Human Necessities – 61 – K
Patent
A - Human Necessities
61
K
A61K 48/00 (2006.01) A61K 31/56 (2006.01) A61K 31/565 (2006.01) A61K 31/7052 (2006.01) C12N 15/11 (2006.01) A61K 38/00 (2006.01) A61K 39/00 (2006.01)
Patent
CA 2365811
Restenosis is a major limitation of percutaneous coronary intervention. Migration and proliferation of vascular cells remain a cornerstone in neointimal formation and vascular healing. Recently, we have shown that local delivery of 17-beta-estradiol (17.beta.E) prevents restenosis following angioplasty by improving vascular healing. Indeed, 17.beta.E inhibited muscle cell proliferation but, on the contrary, favorized the endothelial cell proliferation and function. We herein investigate the effect of an acute administration of 17.beta.E on mitogen-activated protein kinase (MAPK) activity, migration and proliferation of porcine aortic endothelial cells (PAEC) and smooth muscle cells (PSMC). On cultured PAEC and PSMC, we evaluated the effect of 17.beta.E (10 -10 to 10 -7 M) ~ selective 17.beta.E antagonists (Tamoxifen (Tam), 4OH-Tamoxifen (4OH-Tam) and Raloxifen (Ral)) on cell migration and proliferation. The results suggest that in PSMC, chemotatic and mitogenic effect of PDGF-BB as well as p38 and p42/44 MAPK phosphorylation are inhibited by 17.beta.E. In contrast, 17.beta.E promotes in PAEC the phosphorylation of p42/44 and p38 MAPK as well as the migration and proliferation of these cells. The effects of 17.beta.E are reversed by the antagonists on these markers in both cell types. In conclusion, 17.beta.E may improve the vascular healing process by promoting PAEC proliferation and migration and by inhibiting the same events in PSMC. Since at least two estrogen receptors are (ER .alpha. and ER .beta.) are involved in estrogens activity, we propose to silence with antisense molecules the expression of one or both receptors, alone or in combination with the administration of 17.beta.E, to optimize the effect of estrogens on vascular target cells, as well as on other estrogen- responsive cells.
Institut de Cardiologie
Mccarthy Tetrault Llp
Tanguay Jean-Francois
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