Morelloflavone blocks injury-induced neointimal formation by inhibiting vascular smooth muscle cell migration

Decha Pinkaew, Sung Gook Cho, David Y. Hui, John E. Wiktorowicz, Nongporn Hutadilok-Towatana, Wilawan Mahabusarakam, Moltira Tonganunt, Lewis J. Stafford, Amornrat Phongdara, Mingyao Liu, Kenichi Fujise

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background: In-stent restenosis, or renarrowing within a coronary stent, is the most ominous complication of percutaneous coronary intervention, caused by vascular smooth muscle cell (VSMC) migration into and proliferation in the intima. Although drug-eluting stents reduce restenosis, they delay the tissue healing of the injured arteries. No promising alternative anti-restenosis treatments are currently on the horizon. Methods: In endothelium-denudated mouse carotid arteries, oral morelloflavone-an active ingredient of the Thai medicinal plant Garcinia dulcis-significantly decreased the degree of neointimal hyperplasia, without affecting neointimal cell cycle progression or apoptosis as evaluated by Ki-67 and TUNEL staining, respectively. At the cellular level, morelloflavone robustly inhibited VSMC migration as shown by both scratch wound and invasion assays. In addition, morelloflavone prevented VSMCs from forming lamellipodia, a VSMC migration apparatus. Mechanistically, the inhibition by morelloflavone of VSMC migration was through its negative regulatory effects on several migration-related kinases, including FAK, Src, ERK, and RhoA. Consistently with the animal data, morelloflavone did not affect VSMC cell cycle progression or induce apoptosis. Results: These data suggest that morelloflavone blocks injury-induced neointimal hyperplasia via the inhibition of VSMC migration, without inducing apoptosis or cell cycle arrest. General significance: We propose morelloflavone to be a viable oral agent for the prevention of restenosis, without compromising effects on the integrity and healing of the injured arteries.

Original languageEnglish (US)
Pages (from-to)31-39
Number of pages9
JournalBiochimica et Biophysica Acta - General Subjects
Volume1790
Issue number1
DOIs
StatePublished - Jan 2009

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Vascular Smooth Muscle
Smooth Muscle Myocytes
Cell Movement
Muscle
Cells
Wounds and Injuries
Stents
Apoptosis
Hyperplasia
Cell Cycle
Arteries
Garcinia
Pseudopodia
Drug-Eluting Stents
In Situ Nick-End Labeling
Percutaneous Coronary Intervention
Medicinal Plants
Cell Cycle Checkpoints
morelloflavone
Carotid Arteries

Keywords

  • Garcinia dulcis
  • Migration
  • Morelloflavone
  • Restenosis
  • Vascular smooth muscle cell

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Morelloflavone blocks injury-induced neointimal formation by inhibiting vascular smooth muscle cell migration. / Pinkaew, Decha; Cho, Sung Gook; Hui, David Y.; Wiktorowicz, John E.; Hutadilok-Towatana, Nongporn; Mahabusarakam, Wilawan; Tonganunt, Moltira; Stafford, Lewis J.; Phongdara, Amornrat; Liu, Mingyao; Fujise, Kenichi.

In: Biochimica et Biophysica Acta - General Subjects, Vol. 1790, No. 1, 01.2009, p. 31-39.

Research output: Contribution to journalArticle

Pinkaew, D, Cho, SG, Hui, DY, Wiktorowicz, JE, Hutadilok-Towatana, N, Mahabusarakam, W, Tonganunt, M, Stafford, LJ, Phongdara, A, Liu, M & Fujise, K 2009, 'Morelloflavone blocks injury-induced neointimal formation by inhibiting vascular smooth muscle cell migration', Biochimica et Biophysica Acta - General Subjects, vol. 1790, no. 1, pp. 31-39. https://doi.org/10.1016/j.bbagen.2008.09.006
Pinkaew, Decha ; Cho, Sung Gook ; Hui, David Y. ; Wiktorowicz, John E. ; Hutadilok-Towatana, Nongporn ; Mahabusarakam, Wilawan ; Tonganunt, Moltira ; Stafford, Lewis J. ; Phongdara, Amornrat ; Liu, Mingyao ; Fujise, Kenichi. / Morelloflavone blocks injury-induced neointimal formation by inhibiting vascular smooth muscle cell migration. In: Biochimica et Biophysica Acta - General Subjects. 2009 ; Vol. 1790, No. 1. pp. 31-39.
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AU - Cho, Sung Gook

AU - Hui, David Y.

AU - Wiktorowicz, John E.

AU - Hutadilok-Towatana, Nongporn

AU - Mahabusarakam, Wilawan

AU - Tonganunt, Moltira

AU - Stafford, Lewis J.

AU - Phongdara, Amornrat

AU - Liu, Mingyao

AU - Fujise, Kenichi

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N2 - Background: In-stent restenosis, or renarrowing within a coronary stent, is the most ominous complication of percutaneous coronary intervention, caused by vascular smooth muscle cell (VSMC) migration into and proliferation in the intima. Although drug-eluting stents reduce restenosis, they delay the tissue healing of the injured arteries. No promising alternative anti-restenosis treatments are currently on the horizon. Methods: In endothelium-denudated mouse carotid arteries, oral morelloflavone-an active ingredient of the Thai medicinal plant Garcinia dulcis-significantly decreased the degree of neointimal hyperplasia, without affecting neointimal cell cycle progression or apoptosis as evaluated by Ki-67 and TUNEL staining, respectively. At the cellular level, morelloflavone robustly inhibited VSMC migration as shown by both scratch wound and invasion assays. In addition, morelloflavone prevented VSMCs from forming lamellipodia, a VSMC migration apparatus. Mechanistically, the inhibition by morelloflavone of VSMC migration was through its negative regulatory effects on several migration-related kinases, including FAK, Src, ERK, and RhoA. Consistently with the animal data, morelloflavone did not affect VSMC cell cycle progression or induce apoptosis. Results: These data suggest that morelloflavone blocks injury-induced neointimal hyperplasia via the inhibition of VSMC migration, without inducing apoptosis or cell cycle arrest. General significance: We propose morelloflavone to be a viable oral agent for the prevention of restenosis, without compromising effects on the integrity and healing of the injured arteries.

AB - Background: In-stent restenosis, or renarrowing within a coronary stent, is the most ominous complication of percutaneous coronary intervention, caused by vascular smooth muscle cell (VSMC) migration into and proliferation in the intima. Although drug-eluting stents reduce restenosis, they delay the tissue healing of the injured arteries. No promising alternative anti-restenosis treatments are currently on the horizon. Methods: In endothelium-denudated mouse carotid arteries, oral morelloflavone-an active ingredient of the Thai medicinal plant Garcinia dulcis-significantly decreased the degree of neointimal hyperplasia, without affecting neointimal cell cycle progression or apoptosis as evaluated by Ki-67 and TUNEL staining, respectively. At the cellular level, morelloflavone robustly inhibited VSMC migration as shown by both scratch wound and invasion assays. In addition, morelloflavone prevented VSMCs from forming lamellipodia, a VSMC migration apparatus. Mechanistically, the inhibition by morelloflavone of VSMC migration was through its negative regulatory effects on several migration-related kinases, including FAK, Src, ERK, and RhoA. Consistently with the animal data, morelloflavone did not affect VSMC cell cycle progression or induce apoptosis. Results: These data suggest that morelloflavone blocks injury-induced neointimal hyperplasia via the inhibition of VSMC migration, without inducing apoptosis or cell cycle arrest. General significance: We propose morelloflavone to be a viable oral agent for the prevention of restenosis, without compromising effects on the integrity and healing of the injured arteries.

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