BACKGROUND: Cell-specific inhibition of vascular smooth muscle cells, the primary constituent of neointima following arterial injury, without deleterious effects on vascular endothelial cell function may be a critical requirement for drug-eluting stents that are not prone to excess late thrombosis. We hypothesized that imatinib mesylate (Gleevec, Glivec, formerly known as STI571), a relatively selective inhibitor of protein tyrosine kinases including platelet-derived growth factor receptor (PDGFR), would inhibit hCASMC proliferation and migration in vitro with little effect on endothelial cell proliferation and prevent restenosis in a swine balloon injury model. METHODS: Proliferation and migration of stimulated human vascular smooth muscle and endothelial cells were quantified in cell culture in the presence of imatinib (0.001 to 10 M). Imatinib-loaded drug-eluting stents were implanted in swine coronary arteries after predilatation with an oversized balloon, and neointimal proliferation was measured by quantitative angiography and histopathology. RESULTS: Increasing doses of imatinib-inhibited autophosphorylation of the PDGFR and its downstream effects of proliferation and migration of human CASMC in a dose-responsive manner, yet had no effect on stimulated human aortic endothelial cells. However, imatinib-eluting stents had no effect on neointimal proliferation and restenosis in a standard porcine in-stent restenosis model compared to bare-metal or unloaded polymer-coated stents. CONCLUSION: We conclude that imatinib is a potent inhibitor of proliferation and migration of human vascular smooth muscle cells in vitro, but has no effect on human vascular endothelial cell proliferation. However, the lack of an in vivo effect on neointimal proliferation in a standard porcine coronary overstretch model does not support the use of imatinib mesylate for localized drug delivery in the prevention of in-stent restenosis.
BACKGROUND: Cell-specific inhibition of vascular smooth muscle cells, the primary constituent of neointima following arterial injury, without deleterious effects on vascular endothelial cell function may be a critical requirement for drug-eluting stents that are not prone to excess late thrombosis. We hypothesized that imatinib mesylate (Gleevec, Glivec, formerly known as STI571), a relatively selective inhibitor of protein tyrosine kinases including platelet-derived growth factor receptor (PDGFR), would inhibit hCASMC proliferation and migration in vitro with little effect on endothelial cell proliferation and prevent restenosis in a swineballoon injury model. METHODS: Proliferation and migration of stimulated human vascular smooth muscle and endothelial cells were quantified in cell culture in the presence of imatinib (0.001 to 10 M). Imatinib-loaded drug-eluting stents were implanted in swine coronary arteries after predilatation with an oversized balloon, and neointimal proliferation was measured by quantitative angiography and histopathology. RESULTS: Increasing doses of imatinib-inhibited autophosphorylation of the PDGFR and its downstream effects of proliferation and migration of humanCASMC in a dose-responsive manner, yet had no effect on stimulated human aortic endothelial cells. However, imatinib-eluting stents had no effect on neointimal proliferation and restenosis in a standard porcine in-stent restenosis model compared to bare-metal or unloaded polymer-coated stents. CONCLUSION: We conclude that imatinib is a potent inhibitor of proliferation and migration of human vascular smooth muscle cells in vitro, but has no effect on human vascular endothelial cell proliferation. However, the lack of an in vivo effect on neointimal proliferation in a standard porcine coronary overstretch model does not support the use of imatinib mesylate for localized drug delivery in the prevention of in-stent restenosis.
Authors: Alice Chanakira; Raini Dutta; Richard Charboneau; Roderick Barke; Steven M Santilli; Sabita Roy Journal: Am J Physiol Heart Circ Physiol Date: 2011-12-09 Impact factor: 4.733
Authors: Shakti A Goel; Lian-Wang Guo; Bowen Wang; Song Guo; Drew Roenneburg; Gene E Ananiev; F Michael Hoffmann; K Craig Kent Journal: PLoS One Date: 2014-02-24 Impact factor: 3.240