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

Kyung Woo Park, Han Mo Yang, Seock Won Youn, Hyun Ju Yang, In Ho Chae, Byung Hee Oh, Myoung Mook Lee, Young Bae Park, Yun Shik Choi, Hyo Soo Kim, Kenneth Walsh

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1364-1369
Number of pages6
JournalArteriosclerosis, thrombosis, and vascular biology
Volume23
Issue number8
DOIs
StatePublished - Aug 1 2003

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Glycogen Synthase Kinase 3
Neointima
Vascular Smooth Muscle
Smooth Muscle Myocytes
Apoptosis
Wounds and Injuries
Genes
Tunica Intima
Smooth Muscle
Angioplasty
Glycogen Synthase Kinases
Alanine
Serine
Hyperplasia
Catheters
Staining and Labeling

Keywords

  • Glycogen synthase kinase-3β
  • Neointima
  • Vascular smooth muscle

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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. / Park, Kyung Woo; Yang, Han Mo; Youn, Seock Won; Yang, Hyun Ju; Chae, In Ho; Oh, Byung Hee; Lee, Myoung Mook; Park, Young Bae; Choi, Yun Shik; Kim, Hyo Soo; Walsh, Kenneth.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 23, No. 8, 01.08.2003, p. 1364-1369.

Research output: Contribution to journalArticle

Park, Kyung Woo ; Yang, Han Mo ; Youn, Seock Won ; Yang, Hyun Ju ; Chae, In Ho ; Oh, Byung Hee ; Lee, Myoung Mook ; Park, Young Bae ; Choi, Yun Shik ; Kim, Hyo Soo ; Walsh, Kenneth. / 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. In: Arteriosclerosis, thrombosis, and vascular biology. 2003 ; Vol. 23, No. 8. pp. 1364-1369.
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title = "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",
abstract = "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.",
keywords = "Glycogen synthase kinase-3β, Neointima, Vascular smooth muscle",
author = "Park, {Kyung Woo} and Yang, {Han Mo} and Youn, {Seock Won} and Yang, {Hyun Ju} and Chae, {In Ho} and Oh, {Byung Hee} and Lee, {Myoung Mook} and Park, {Young Bae} and Choi, {Yun Shik} and Kim, {Hyo Soo} and Kenneth Walsh",
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language = "English (US)",
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number = "8",

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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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