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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1364.)
© 2003 American Heart Association, Inc.

Vascular Biology

Constitutively Active Glycogen Synthase Kinase-3ß 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

From the Cardiovascular Laboratory (K.-W.P., H.-M.Y., S.-W.Y., H.-J.Y., I.-H.C., B.-H.O., M.-M.L., Y.-B.P., Y.-S.C., H.-S.K.), Clinical Research Institute, Seoul National University Hospital, Korea; Department of Internal Medicine (K.-W.P., H.-M.Y., I.-H.C., B.-H.O., M.-M.L., Y.-B.P., T.-S.C., H.-S.K.), Seoul National University College of Medicine, Korea; and Whitaker Cardiovascular Institute (H.-S.K., K.W.), Boston University School of Medicine, Boston, Mass.

Correspondence to Hyo-Soo Kim, MD, PhD, Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong Chongno-gu, Seoul 110-744, Korea. E-mail hyosoo{at}snu.ac.kr

Objective— Glycogen synthase kinase (GSK)-3ß 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-3ß 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-3ß (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 (5x10⁸ 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-3ß 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-3ß 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-3ß 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-3ß gene transfer).

Conclusions— In vivo delivery of the active GSK-3ß 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.

Key Words: glycogen synthase kinase-3ß • vascular smooth muscle • neointima

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