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

Jonathan A. Hata, Jason A. Petrofski, Jacob N. Schroder, Matthew L. Williams, Sarah H. Timberlake, Anne Pippen, Michael T Corwin, Amy K. Solan, Andre Jakoi, Thomas R. Gehrig, Christopher D. Kontos, Carmelo A. Milano

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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 (β-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 mm2, 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.

Original languageEnglish (US)
Pages (from-to)1405-1413
Number of pages9
JournalJournal of Thoracic and Cardiovascular Surgery
Volume129
Issue number6
DOIs
StatePublished - Jun 2005
Externally publishedYes

Fingerprint

Phosphatidylinositol 3-Kinase
Tunica Intima
Saphenous Vein
Hyperplasia
Transplants
Adenoviridae
Vascular Smooth Muscle
Smooth Muscle Myocytes
Platelet-Derived Growth Factor
Transgenes
Immunoblotting
Coronary Artery Bypass
Phosphates
Cell Proliferation
Galactosidases
PTEN Phosphohydrolase
Chromosomes, Human, Pair 10

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

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. Journal of Thoracic and Cardiovascular Surgery, 129(6), 1405-1413. https://doi.org/10.1016/j.jtcvs.2004.11.048

Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts. / Hata, Jonathan A.; Petrofski, Jason A.; Schroder, Jacob N.; Williams, Matthew L.; Timberlake, Sarah H.; Pippen, Anne; Corwin, Michael T; Solan, Amy K.; Jakoi, Andre; Gehrig, Thomas R.; Kontos, Christopher D.; Milano, Carmelo A.

In: Journal of Thoracic and Cardiovascular Surgery, Vol. 129, No. 6, 06.2005, p. 1405-1413.

Research output: Contribution to journalArticle

Hata, JA, Petrofski, JA, Schroder, JN, Williams, ML, Timberlake, SH, Pippen, A, Corwin, MT, Solan, AK, Jakoi, A, Gehrig, TR, Kontos, CD & Milano, CA 2005, 'Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts', Journal of Thoracic and Cardiovascular Surgery, vol. 129, no. 6, pp. 1405-1413. https://doi.org/10.1016/j.jtcvs.2004.11.048
Hata, Jonathan A. ; Petrofski, Jason A. ; Schroder, Jacob N. ; Williams, Matthew L. ; Timberlake, Sarah H. ; Pippen, Anne ; Corwin, Michael T ; Solan, Amy K. ; Jakoi, Andre ; Gehrig, Thomas R. ; Kontos, Christopher D. ; Milano, Carmelo A. / Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts. In: Journal of Thoracic and Cardiovascular Surgery. 2005 ; Vol. 129, No. 6. pp. 1405-1413.
@article{f49fc0306693497080eab317c67e0889,
title = "Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts",
abstract = "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 (β-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 mm2, 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.",
author = "Hata, {Jonathan A.} and Petrofski, {Jason A.} and Schroder, {Jacob N.} and Williams, {Matthew L.} and Timberlake, {Sarah H.} and Anne Pippen and Corwin, {Michael T} and Solan, {Amy K.} and Andre Jakoi and Gehrig, {Thomas R.} and Kontos, {Christopher D.} and Milano, {Carmelo A.}",
year = "2005",
month = "6",
doi = "10.1016/j.jtcvs.2004.11.048",
language = "English (US)",
volume = "129",
pages = "1405--1413",
journal = "Journal of Thoracic and Cardiovascular Surgery",
issn = "0022-5223",
publisher = "Mosby Inc.",
number = "6",

}

TY - JOUR

T1 - Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts

AU - Hata, Jonathan A.

AU - Petrofski, Jason A.

AU - Schroder, Jacob N.

AU - Williams, Matthew L.

AU - Timberlake, Sarah H.

AU - Pippen, Anne

AU - Corwin, Michael T

AU - Solan, Amy K.

AU - Jakoi, Andre

AU - Gehrig, Thomas R.

AU - Kontos, Christopher D.

AU - Milano, Carmelo A.

PY - 2005/6

Y1 - 2005/6

N2 - 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 (β-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 mm2, 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.

AB - 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 (β-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 mm2, 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.

UR - http://www.scopus.com/inward/record.url?scp=20444391695&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20444391695&partnerID=8YFLogxK

U2 - 10.1016/j.jtcvs.2004.11.048

DO - 10.1016/j.jtcvs.2004.11.048

M3 - Article

VL - 129

SP - 1405

EP - 1413

JO - Journal of Thoracic and Cardiovascular Surgery

JF - Journal of Thoracic and Cardiovascular Surgery

SN - 0022-5223

IS - 6

ER -