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Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts.

Publication ,  Journal Article
Hata, JA; Petrofski, JA; Schroder, JN; Williams, ML; Timberlake, SH; Pippen, A; Corwin, MT; Solan, AK; Jakoi, A; Gehrig, TR; Kontos, CD; Milano, CA
Published in: J Thorac Cardiovasc Surg
June 2005

OBJECTIVES: Fifty percent of human aortocoronary saphenous vein grafts are occluded after 10 years. Intimal hyperplasia is an initial step in graft occlusion and consists of vascular smooth muscle cell proliferation. Phosphatidylinositol 3-kinase and its downstream regulator, the inositol 3-phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10), are important regulators of vascular smooth muscle cell proliferation, migration, and cell death. This study tests whether overexpression of PTEN in aortocoronary saphenous vein grafts can reduce intimal hyperplasia. METHODS: Adult dogs underwent aortocoronary bypass grafting to the left anterior descending artery by using the autologous saphenous vein. Saphenous vein grafts were treated with phosphate-buffered saline (n = 9), empty adenovirus (n = 8), or adenovirus encoding for PTEN (n = 8). Arteriography at 30 and 90 days assessed saphenous vein graft patency. A subset received saphenous vein grafts treated with a marker transgene (beta-galactosidase, n = 3), empty adenovirus (n = 4), or adenovirus encoding for PTEN (n = 4) and were killed on postoperative day 3 to confirm expression. Vascular smooth muscle cells were isolated from canine saphenous vein infected with adenovirus encoding for PTEN, and immunoblotting and proliferation assays were performed. RESULTS: Saphenous vein graft transgene expression was confirmed by means of immunohistochemistry, immunoblotting, and polymerase chain reaction. Arteriograms revealed all saphenous vein grafts to be patent. Saphenous vein grafts treated with adenovirus encoding for PTEN demonstrated reduced intimal area compared with those treated with empty adenovirus and phosphate-buffered saline (1.39 +/- 0.11 vs 2.35 +/- 0.3 and 2.57 +/- 0.4 mm 2 , P < .05), and the intima/media ratio was lower in saphenous vein grafts treated with adenovirus encoding for PTEN (0.50 +/- 0.05 vs 1.43 +/- 0.18 and 1.11 +/- 0.14, P < .005). PTEN overexpression in vascular smooth muscle cells inhibited platelet-derived growth factor-induced phosphorylation of Akt, a downstream effector of phosphatidylinositol 3-kinase. PTEN-treated vascular smooth muscle cells demonstrated decreased basal, platelet-derived growth factor-stimulated, and serum-stimulated proliferation. CONCLUSION: This study demonstrates that PTEN overexpression in aortocoronary saphenous vein grafts reduces intimal hyperplasia. The mechanism of this antiproliferative effect in vascular smooth muscle cells is likely due to inhibition of phosphatidylinositol 3-kinase signaling through Akt, with resultant decreases in vascular smooth muscle cell growth and survival. Therefore modulation of the phosphatidylinositol 3-kinase pathway through PTEN overexpression might represent a novel therapy to prevent saphenous vein graft intimal hyperplasia after coronary artery bypass grafting.

Duke Scholars

Published In

J Thorac Cardiovasc Surg

DOI

ISSN

0022-5223

Publication Date

June 2005

Volume

129

Issue

6

Start / End Page

1405 / 1413

Location

United States

Related Subject Headings

  • Tunica Intima
  • Signal Transduction
  • Saphenous Vein
  • Respiratory System
  • Phosphatidylinositol 3-Kinases
  • Muscle, Smooth, Vascular
  • Hyperplasia
  • Graft Occlusion, Vascular
  • Dogs
  • Coronary Artery Bypass
 

Citation

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Hata, J. A., Petrofski, J. A., Schroder, J. N., Williams, M. L., Timberlake, S. H., Pippen, A., … Milano, C. A. (2005). Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts. J Thorac Cardiovasc Surg, 129(6), 1405–1413. https://doi.org/10.1016/j.jtcvs.2004.11.048
Hata, Jonathan A., Jason A. Petrofski, Jacob N. Schroder, Matthew L. Williams, Sarah H. Timberlake, Anne Pippen, Michael T. Corwin, et al. “Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts.J Thorac Cardiovasc Surg 129, no. 6 (June 2005): 1405–13. https://doi.org/10.1016/j.jtcvs.2004.11.048.
Hata JA, Petrofski JA, Schroder JN, Williams ML, Timberlake SH, Pippen A, et al. Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts. J Thorac Cardiovasc Surg. 2005 Jun;129(6):1405–13.
Hata, Jonathan A., et al. “Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts.J Thorac Cardiovasc Surg, vol. 129, no. 6, June 2005, pp. 1405–13. Pubmed, doi:10.1016/j.jtcvs.2004.11.048.
Hata JA, Petrofski JA, Schroder JN, Williams ML, Timberlake SH, Pippen A, Corwin MT, Solan AK, Jakoi A, Gehrig TR, Kontos CD, Milano CA. Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts. J Thorac Cardiovasc Surg. 2005 Jun;129(6):1405–1413.
Journal cover image

Published In

J Thorac Cardiovasc Surg

DOI

ISSN

0022-5223

Publication Date

June 2005

Volume

129

Issue

6

Start / End Page

1405 / 1413

Location

United States

Related Subject Headings

  • Tunica Intima
  • Signal Transduction
  • Saphenous Vein
  • Respiratory System
  • Phosphatidylinositol 3-Kinases
  • Muscle, Smooth, Vascular
  • Hyperplasia
  • Graft Occlusion, Vascular
  • Dogs
  • Coronary Artery Bypass