TY - JOUR
T1 - Esculetin inhibits Ras-mediated cell proliferation and attenuates vascular restenosis following angioplasty in rats
AU - Pan, Shiow Lin
AU - Huang, Ying Wen
AU - Guh, Jih Hwa
AU - Chang, Ya Ling
AU - Peng, Chieh Yu
AU - Teng, Che Ming
N1 - Funding Information:
This work was supported by a research grant from the National Science Council of the Republic of China (NSC90-2315-B-002-003).
PY - 2003/6/1
Y1 - 2003/6/1
N2 - 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.
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.
KW - Esculetin
KW - Proliferation
KW - Ras
KW - Restenosis
KW - Smooth muscle cells
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U2 - 10.1016/S0006-2952(03)00161-8
DO - 10.1016/S0006-2952(03)00161-8
M3 - Article
C2 - 12781342
AN - SCOPUS:0037716437
SN - 0006-2952
VL - 65
SP - 1897
EP - 1905
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 11
ER -