Esculetin inhibits Ras-mediated cell proliferation and attenuates vascular restenosis following angioplasty in rats

Shiow Lin Pan, Ying Wen Huang, Jih Hwa Guh, Ya Ling Chang, Chieh Yu Peng, Che Ming Teng

Research output: Contribution to journalArticle

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Abstract

The proliferation of vascular smooth muscle cells (VSMCs) induced by injury to the intima of arteries is an important etiologic factor in vascular proliferative disorders such as atherosclerosis and restenosis. Esculetin, derived from the Chinese herb Artemisia scoparia, is well known as a lipoxygenase inhibitor. We have investigated the inhibitory effects of esculetin on VSMC proliferation and intimal hyperplasia by balloon angioplasty in the rat. We determined, using [3H]thymidine incorporation and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, that esculetin inhibited the proliferation of VSMCs via a lipoxygenase-independent pathway. Three predominant signaling pathways were identified to be inhibited by esculetin: (a) the activation of p42/44 mitogen-activated protein kinase (MAPK) and the downstream effectors of c-fos and c-jun immediate early genes by means of western and reverse transcription-polymerase chain reaction (RT-PCR) analyses; (b) the activation of nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), using the electrophoretic mobility shift assay; and (c) the activation of phosphoinositide 3-kinase (PI 3-kinase) and cell cycle progression, by western blot analysis and flow cytometric detection. Furthermore, esculetin also profoundly inhibited Ras activation, a shared upstream event of the above signaling cascades. In vascular injury studies, intraperitoneal administration of esculetin significantly suppressed intimal hyperplasia induced by balloon angioplasty. We conclude that esculetin blocks cell proliferation via the inhibition of an upstream effector of Ras and downstream events including p42/44 MAPK activation, PI 3-kinase activation, immediate early gene expression, as well as NF-κB and AP-1 activation. It also inhibits intimal hyperplasia after balloon vascular injury in the rat, indicating the therapeutic potential for treating restenosis after arterial injury.

Original languageEnglish
Pages (from-to)1897-1905
Number of pages9
JournalBiochemical Pharmacology
Volume65
Issue number11
DOIs
Publication statusPublished - Jun 1 2003
Externally publishedYes

Fingerprint

Cell proliferation
Angioplasty
Blood Vessels
Rats
Chemical activation
Cell Proliferation
Tunica Intima
Balloons
Vascular Smooth Muscle
Smooth Muscle Myocytes
Hyperplasia
Muscle
Immediate-Early Genes
1-Phosphatidylinositol 4-Kinase
Balloon Angioplasty
Vascular System Injuries
Mitogen-Activated Protein Kinase 1
Transcription Factor AP-1
Phosphatidylinositols
Mitogen-Activated Protein Kinases

Keywords

  • Esculetin
  • Proliferation
  • Ras
  • Restenosis
  • Smooth muscle cells

ASJC Scopus subject areas

  • Pharmacology

Cite this

Esculetin inhibits Ras-mediated cell proliferation and attenuates vascular restenosis following angioplasty in rats. / Pan, Shiow Lin; Huang, Ying Wen; Guh, Jih Hwa; Chang, Ya Ling; Peng, Chieh Yu; Teng, Che Ming.

In: Biochemical Pharmacology, Vol. 65, No. 11, 01.06.2003, p. 1897-1905.

Research output: Contribution to journalArticle

Pan, Shiow Lin ; Huang, Ying Wen ; Guh, Jih Hwa ; Chang, Ya Ling ; Peng, Chieh Yu ; Teng, Che Ming. / Esculetin inhibits Ras-mediated cell proliferation and attenuates vascular restenosis following angioplasty in rats. In: Biochemical Pharmacology. 2003 ; Vol. 65, No. 11. pp. 1897-1905.
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AU - Peng, Chieh Yu

AU - Teng, Che Ming

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AB - The proliferation of vascular smooth muscle cells (VSMCs) induced by injury to the intima of arteries is an important etiologic factor in vascular proliferative disorders such as atherosclerosis and restenosis. Esculetin, derived from the Chinese herb Artemisia scoparia, is well known as a lipoxygenase inhibitor. We have investigated the inhibitory effects of esculetin on VSMC proliferation and intimal hyperplasia by balloon angioplasty in the rat. We determined, using [3H]thymidine incorporation and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, that esculetin inhibited the proliferation of VSMCs via a lipoxygenase-independent pathway. Three predominant signaling pathways were identified to be inhibited by esculetin: (a) the activation of p42/44 mitogen-activated protein kinase (MAPK) and the downstream effectors of c-fos and c-jun immediate early genes by means of western and reverse transcription-polymerase chain reaction (RT-PCR) analyses; (b) the activation of nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), using the electrophoretic mobility shift assay; and (c) the activation of phosphoinositide 3-kinase (PI 3-kinase) and cell cycle progression, by western blot analysis and flow cytometric detection. Furthermore, esculetin also profoundly inhibited Ras activation, a shared upstream event of the above signaling cascades. In vascular injury studies, intraperitoneal administration of esculetin significantly suppressed intimal hyperplasia induced by balloon angioplasty. We conclude that esculetin blocks cell proliferation via the inhibition of an upstream effector of Ras and downstream events including p42/44 MAPK activation, PI 3-kinase activation, immediate early gene expression, as well as NF-κB and AP-1 activation. It also inhibits intimal hyperplasia after balloon vascular injury in the rat, indicating the therapeutic potential for treating restenosis after arterial injury.

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