on June 12, 2003
Published online before print June 12, 2003, doi: 10.1161/01.ATV.0000081633.53390.B4
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on January 28, 2003
Accepted on May 11, 2003
Constitutively Active Glycogen Synthase Kinase-3
Gene Transfer Sustains Apoptosis, Inhibits Proliferation of Vascular Smooth Muscle Cells, and Reduces Neointima Formation After Balloon Injury in Rats
Kyung-Woo Park ;
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.
* To whom correspondence should be addressed. E-mail: hyosoo{at}snu.ac.kr.
Objective--Glycogen synthase kinase (GSK)-3
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-3 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-3 (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-3 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-3 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-3 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-3 gene transfer).
Conclusions--In vivo delivery of the active GSK-3 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-3
•
vascular smooth muscle •
neointima
This article has been cited by other articles:
 |
|
 |
|
  S. Bonnet, R. Paulin, G. Sutendra, P. Dromparis, M. Roy, K. O. Watson, J. Nagendran, A. Haromy, J. R.B. Dyck, and E. D. Michelakis Dehydroepiandrosterone Reverses Systemic Vascular Remodeling Through the Inhibition of the Akt/GSK3-{beta}/NFAT Axis Circulation, September 29, 2009; 120(13): 1231 - 1240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-Y. Kim, H.-J. Cho, J.-J. Sir, B.-K. Kim, J. Hur, S.-W. Youn, H.-M. Yang, S.-I. Jun, K.-W. Park, S.-J. Hwang, et al. Sulfasalazine induces haem oxygenase-1 via ROS-dependent Nrf2 signalling, leading to control of neointimal hyperplasia Cardiovasc Res, June 1, 2009; 82(3): 550 - 560. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-S. Lee, Y.-W. Kwon, H.-M. Yang, S.-H. Kim, T.-Y. Kim, J. Hur, K.-W. Park, H.-J. Cho, H.-J. Kang, Y.-B. Park, et al. New Mechanism of Rosiglitazone to Reduce Neointimal Hyperplasia: Activation of Glycogen Synthase Kinase-3{beta} Followed by Inhibition of MMP-9 Arterioscler Thromb Vasc Biol, April 1, 2009; 29(4): 472 - 479. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-Y. Lee, J.-W. Chung, S.-W. Youn, J.-Y. Kim, K.-W. Park, B.-K. Koo, B.-H. Oh, Y.-B. Park, B. Chaqour, K. Walsh, et al. Forkhead Transcription Factor FOXO3a Is a Negative Regulator of Angiogenic Immediate Early Gene CYR61, Leading to Inhibition of Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia Circ. Res., February 16, 2007; 100(3): 372 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-Y. Hahn, H.-J. Cho, J.-W. Bae, H.-S. Yuk, K.-i. Kim, K.-W. Park, B.-K. Koo, I.-H. Chae, C.-S. Shin, B.-H. Oh, et al. beta-Catenin Overexpression Reduces Myocardial Infarct Size through Differential Effects on Cardiomyocytes and Cardiac Fibroblasts J. Biol. Chem., October 13, 2006; 281(41): 30979 - 30989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Lim, C. J. Jin, M. Kim, S. S. Chung, H. S. Park, I. K. Lee, C. T. Lee, Y. M. Cho, H. K. Lee, and K. S. Park PPAR{gamma} Gene Transfer Sustains Apoptosis, Inhibits Vascular Smooth Muscle Cell Proliferation, and Reduces Neointima Formation After Balloon Injury in Rats Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 808 - 813. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-W. Park, D.-H. Kim, H.-J. You, J.-J. Sir, S.-I. Jeon, S.-W. Youn, H.-M. Yang, C. Skurk, Y.-B. Park, K. Walsh, et al. Activated Forkhead Transcription Factor Inhibits Neointimal Hyperplasia After Angioplasty Through Induction of p27 Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 742 - 747. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-H. Choi, J. Hur, C.-H. Yoon, J.-H. Kim, C.-S. Lee, S.-W. Youn, I.-Y. Oh, C. Skurk, T. Murohara, Y.-B. Park, et al. Augmentation of Therapeutic Angiogenesis Using Genetically Modified Human Endothelial Progenitor Cells with Altered Glycogen Synthase Kinase-3{beta} Activity J. Biol. Chem., November 19, 2004; 279(47): 49430 - 49438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-M. Yang, H.-S. Kim, K.-W. Park, H.-J. You, S.-I. Jeon, S.-W. Youn, S.-H. Kim, B.-H. Oh, M.-M. Lee, Y.-B. Park, et al. Celecoxib, a Cyclooxygenase-2 Inhibitor, Reduces Neointimal Hyperplasia Through Inhibition of Akt Signaling Circulation, July 20, 2004; 110(3): 301 - 308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Slater, E. Koutsouki, C. L. Jackson, R. C. Bush, G. D. Angelini, A. C. Newby, and S. J. George R-Cadherin:{beta}-Catenin Complex and Its Association With Vascular Smooth Muscle Cell Proliferation Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1204 - 1210. [Abstract] [Full Text] [PDF]
|
|