Celecoxib, a cyclooxygenase-2 inhibitor, reduces neointimal hyperplasia through inhibition of Akt signaling

Han Mo Yang, Hyo Soo Kim, Kyung Woo Park, Hyun Jeong You, Soo In Jeon, Seock Won Youn, Sung Hwan Kim, Byung Hee Oh, Myoung Mook Lee, Young Bae Park, Kenneth Walsh

Research output: Contribution to journalArticle

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Abstract

Background-Celecoxib has been shown to have antitumor effects that may be mediated through the cyclooxygenase-independent inhibition of Akt signaling. Here, we examined the effects of celecoxib on neointimal formation after balloon injury and its mechanism of action. Methods and Results-In vitro experiments were performed to evaluate the effects of celecoxib on the Akt/GSK signaling axis and the viability of rat vascular smooth muscle cells (VSMCs). In vivo experiments examined the effects of celecoxib, aspirin, and vehicle on neointimal growth after denudation injury to rat carotid arteries. In vitro, celecoxib suppressed the phosphorylation of Akt and GSK in cultured VSMCs, leading to a reduction in viable cell number, which was reversed by transduction of constitutively active Akt. Such a reduction in cell number was mediated by inhibition of proliferation and induction of apoptosis. In vivo, celecoxib reduced injury-induced phosphorylation of Akt and GSK, reduced VSMC proliferation, and increased caspase-3 activation and VSMC apoptosis at 3 days after injury, whereas aspirin had no effect. At 2 weeks after injury, celecoxib reduced intima-to-media ratio, whereas aspirin had no effect. Adenovirus-mediated delivery of dominant negative Akt was as effective as celecoxib at inhibiting neointimal formation. Conversely, gene delivery of constitutively active Akt significantly reversed the inhibition of intimal hyperplasia by celecoxib, providing causal evidence that the modulation of Akt signaling by celecoxib is a physiologically relevant mechanism. Conclusions-Celecoxib is a potential inhibitor of neointimal formation by blocking injury-induced Akt activation. These findings suggest a potential use for celecoxib in the prevention of restenosis after angioplasty.

Original languageEnglish (US)
Pages (from-to)301-308
Number of pages8
JournalCirculation
Volume110
Issue number3
DOIs
StatePublished - Jul 20 2004

Fingerprint

Celecoxib
Cyclooxygenase 2 Inhibitors
Hyperplasia
Vascular Smooth Muscle
Smooth Muscle Myocytes
Wounds and Injuries
Aspirin
Cell Count
Phosphorylation
Tunica Intima
Apoptosis

Keywords

  • Akt
  • Apoptosis
  • Cyclooxygenase inhibitors
  • Muscle, smooth
  • Restenosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Yang, H. M., Kim, H. S., Park, K. W., You, H. J., Jeon, S. I., Youn, S. W., ... Walsh, K. (2004). Celecoxib, a cyclooxygenase-2 inhibitor, reduces neointimal hyperplasia through inhibition of Akt signaling. Circulation, 110(3), 301-308. https://doi.org/10.1161/01.CIR.0000135467.43430.16

Celecoxib, a cyclooxygenase-2 inhibitor, reduces neointimal hyperplasia through inhibition of Akt signaling. / Yang, Han Mo; Kim, Hyo Soo; Park, Kyung Woo; You, Hyun Jeong; Jeon, Soo In; Youn, Seock Won; Kim, Sung Hwan; Oh, Byung Hee; Lee, Myoung Mook; Park, Young Bae; Walsh, Kenneth.

In: Circulation, Vol. 110, No. 3, 20.07.2004, p. 301-308.

Research output: Contribution to journalArticle

Yang, HM, Kim, HS, Park, KW, You, HJ, Jeon, SI, Youn, SW, Kim, SH, Oh, BH, Lee, MM, Park, YB & Walsh, K 2004, 'Celecoxib, a cyclooxygenase-2 inhibitor, reduces neointimal hyperplasia through inhibition of Akt signaling', Circulation, vol. 110, no. 3, pp. 301-308. https://doi.org/10.1161/01.CIR.0000135467.43430.16
Yang, Han Mo ; Kim, Hyo Soo ; Park, Kyung Woo ; You, Hyun Jeong ; Jeon, Soo In ; Youn, Seock Won ; Kim, Sung Hwan ; Oh, Byung Hee ; Lee, Myoung Mook ; Park, Young Bae ; Walsh, Kenneth. / Celecoxib, a cyclooxygenase-2 inhibitor, reduces neointimal hyperplasia through inhibition of Akt signaling. In: Circulation. 2004 ; Vol. 110, No. 3. pp. 301-308.
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AU - Jeon, Soo In

AU - Youn, Seock Won

AU - Kim, Sung Hwan

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AB - Background-Celecoxib has been shown to have antitumor effects that may be mediated through the cyclooxygenase-independent inhibition of Akt signaling. Here, we examined the effects of celecoxib on neointimal formation after balloon injury and its mechanism of action. Methods and Results-In vitro experiments were performed to evaluate the effects of celecoxib on the Akt/GSK signaling axis and the viability of rat vascular smooth muscle cells (VSMCs). In vivo experiments examined the effects of celecoxib, aspirin, and vehicle on neointimal growth after denudation injury to rat carotid arteries. In vitro, celecoxib suppressed the phosphorylation of Akt and GSK in cultured VSMCs, leading to a reduction in viable cell number, which was reversed by transduction of constitutively active Akt. Such a reduction in cell number was mediated by inhibition of proliferation and induction of apoptosis. In vivo, celecoxib reduced injury-induced phosphorylation of Akt and GSK, reduced VSMC proliferation, and increased caspase-3 activation and VSMC apoptosis at 3 days after injury, whereas aspirin had no effect. At 2 weeks after injury, celecoxib reduced intima-to-media ratio, whereas aspirin had no effect. Adenovirus-mediated delivery of dominant negative Akt was as effective as celecoxib at inhibiting neointimal formation. Conversely, gene delivery of constitutively active Akt significantly reversed the inhibition of intimal hyperplasia by celecoxib, providing causal evidence that the modulation of Akt signaling by celecoxib is a physiologically relevant mechanism. Conclusions-Celecoxib is a potential inhibitor of neointimal formation by blocking injury-induced Akt activation. These findings suggest a potential use for celecoxib in the prevention of restenosis after angioplasty.

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