TY - JOUR
T1 - Constitutively active glycogen synthase kinase-3β gene transfer sustains apoptosis, inhibits proliferation of vascular smooth muscle cells, and reduces neointima formation after balloon injury in rats
AU - Park, Kyung Woo
AU - Yang, Han Mo
AU - Youn, Seock Won
AU - Yang, Hyun Ju
AU - Chae, In Ho
AU - Oh, Byung Hee
AU - Lee, Myoung Mook
AU - Park, Young Bae
AU - Choi, Yun Shik
AU - Kim, Hyo Soo
AU - Walsh, Kenneth
PY - 2003/8/1
Y1 - 2003/8/1
N2 - Objective - Glycogen synthase kinase (GSK)-3β is a crucial factor in many cellular signaling pathways and may play an important role in smooth muscle proliferation and apoptosis after angioplasty. Methods and Results - To investigate the effect of GSK-3β modulation on neointima formation, smooth muscle proliferation, and apoptosis after balloon injury in vivo, we delivered adenoviral vectors expressing the constitutively active form of GSK-3β (GSK-S9A: 9th serine switched to alanine) or a control gene into rat carotid arterial segments after balloon injury with a 2F Fogarty catheter. Viral infusion mixtures (5×108 pfu) were incubated in the arterial lumen for 20 minutes, and the effects of gene delivery were evaluated 3 days and 2 weeks after gene delivery with morphometry and immunohistochemical staining for proliferating and apoptotic cells. There were no significant differences in intimal, medial, and lumen areas at 3 days after the procedure. However, 2 weeks after gene delivery, the active GSK-3β gene transfer resulted in a significantly lower intima to media ratio (0.29±0.06 versus 0.86±0.09, P<0.01) and a greater lumen area (0.41±0.02 versus 0.31±0.01 mm2, P<0.01) compared with the control gene transfected group. This was attributable to a significant reduction in intimal area (0.05±0.01 versus 0.15±0.02 mm2. P<0.01), whereas the medial area was similar (0.17±0.01 versus 0.18±0.01 mm2, P=0.21). Proliferation index was significantly reduced both at 3 days and 2 weeks in the active GSK-3β gene transferred group (2.97±0.29% versus 5.71±0.50%, P<0.01). In addition, apoptotic index, which was not significantly different between the 2 groups at 3 days, was significantly higher in the active GSK-3β gene transferred group at 2 weeks (3.14±0.68% versus 22.7±1.63%, n= 10, P<0.01, for control versus active GSK-3β gene transfer). Conclusions - In vivo delivery of the active GSK-3β gene inhibits smooth muscle proliferation, sustains apoptosis, and reduces neointima formation after balloon injury in rats and may be a future therapeutic target to limit neointima hyperplasia after angioplasty.
AB - Objective - Glycogen synthase kinase (GSK)-3β is a crucial factor in many cellular signaling pathways and may play an important role in smooth muscle proliferation and apoptosis after angioplasty. Methods and Results - To investigate the effect of GSK-3β modulation on neointima formation, smooth muscle proliferation, and apoptosis after balloon injury in vivo, we delivered adenoviral vectors expressing the constitutively active form of GSK-3β (GSK-S9A: 9th serine switched to alanine) or a control gene into rat carotid arterial segments after balloon injury with a 2F Fogarty catheter. Viral infusion mixtures (5×108 pfu) were incubated in the arterial lumen for 20 minutes, and the effects of gene delivery were evaluated 3 days and 2 weeks after gene delivery with morphometry and immunohistochemical staining for proliferating and apoptotic cells. There were no significant differences in intimal, medial, and lumen areas at 3 days after the procedure. However, 2 weeks after gene delivery, the active GSK-3β gene transfer resulted in a significantly lower intima to media ratio (0.29±0.06 versus 0.86±0.09, P<0.01) and a greater lumen area (0.41±0.02 versus 0.31±0.01 mm2, P<0.01) compared with the control gene transfected group. This was attributable to a significant reduction in intimal area (0.05±0.01 versus 0.15±0.02 mm2. P<0.01), whereas the medial area was similar (0.17±0.01 versus 0.18±0.01 mm2, P=0.21). Proliferation index was significantly reduced both at 3 days and 2 weeks in the active GSK-3β gene transferred group (2.97±0.29% versus 5.71±0.50%, P<0.01). In addition, apoptotic index, which was not significantly different between the 2 groups at 3 days, was significantly higher in the active GSK-3β gene transferred group at 2 weeks (3.14±0.68% versus 22.7±1.63%, n= 10, P<0.01, for control versus active GSK-3β gene transfer). Conclusions - In vivo delivery of the active GSK-3β gene inhibits smooth muscle proliferation, sustains apoptosis, and reduces neointima formation after balloon injury in rats and may be a future therapeutic target to limit neointima hyperplasia after angioplasty.
KW - Glycogen synthase kinase-3β
KW - Neointima
KW - Vascular smooth muscle
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U2 - 10.1161/01.ATV.0000081633.53390.B4
DO - 10.1161/01.ATV.0000081633.53390.B4
M3 - Article
C2 - 12805073
AN - SCOPUS:10744232976
SN - 1079-5642
VL - 23
SP - 1364
EP - 1369
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 8
ER -