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

40 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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