Reactive oxygen species-sensitive p38 MAPK controls thrombin-induced migration of vascular smooth muscle cells

Zhongbiao Wang, Manuel R Castresana, Walter H. Newman

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Thrombin has been implicated in the development of atherosclerosis and restenosis, in which migration of vascular smooth muscle cells (VSMC) is a crucial event. Thrombin-stimulated VSMC migration is associated with increased generation of reactive oxygen species (ROS), activation of mitogen-activated protein kinases (MAPKs), and production of growth factors and chemoattractants. In this study, we examined the interrelation of these signals to determine the pathway controlling thrombin-directed migration of human VSMC. Our results show that thrombin stimulated the production of ROS and activation of p38 MAPK. ROS were required for thrombin-induced VSMC migration since both generation of ROS and cell migration were significantly attenuated by inhibitors of NAD(P)H oxidase, diphenyleneiodonium (DPI) and apocynin (Apo.), and by the hydrogen peroxide scavenger, catalase (Cat.). Activation of p38 MAPK by thrombin was inhibited by DPI, Apo. and Cat., indicating ROS are used as messengers for activating this kinase. p38 MAPK is an important step since SB 203580, a selective inhibitor of p38 MAPK, suppressed the cell migration induced by thrombin. Furthermore, thrombin increased the expression of vascular endothelial growth factor (VEGF), a chemoattractant for VSMC, and this expression was inhibited by DPI, Apo., Cat. and SB 203580. Addition of anti-VEGF antibody significantly attenuated thrombin-induced migration. Collectively, the data presented here show that thrombin has stimulated VSMC migration and VEGF expression through an ROS-sensitive p38 MAPK pathway. VEGF synthesized and released by the cell served as a secondary mediator in thrombin-directed migration.

Original languageEnglish (US)
Pages (from-to)49-56
Number of pages8
JournalJournal of molecular and cellular cardiology
Volume36
Issue number1
DOIs
StatePublished - Jan 1 2004
Externally publishedYes

Fingerprint

p38 Mitogen-Activated Protein Kinases
Vascular Smooth Muscle
Thrombin
Smooth Muscle Myocytes
Reactive Oxygen Species
Cell Movement
Vascular Endothelial Growth Factor A
Catalase
Chemotactic Factors
NADPH Oxidase
Mitogen-Activated Protein Kinases
Hydrogen Peroxide
Atherosclerosis
Intercellular Signaling Peptides and Proteins
Phosphotransferases

Keywords

  • Migration
  • Reactive oxygen species
  • Thrombin
  • Vascular endothelial growth factor
  • Vascular smooth muscle cell
  • p38 MAPK

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Reactive oxygen species-sensitive p38 MAPK controls thrombin-induced migration of vascular smooth muscle cells. / Wang, Zhongbiao; Castresana, Manuel R; Newman, Walter H.

In: Journal of molecular and cellular cardiology, Vol. 36, No. 1, 01.01.2004, p. 49-56.

Research output: Contribution to journalArticle

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abstract = "Thrombin has been implicated in the development of atherosclerosis and restenosis, in which migration of vascular smooth muscle cells (VSMC) is a crucial event. Thrombin-stimulated VSMC migration is associated with increased generation of reactive oxygen species (ROS), activation of mitogen-activated protein kinases (MAPKs), and production of growth factors and chemoattractants. In this study, we examined the interrelation of these signals to determine the pathway controlling thrombin-directed migration of human VSMC. Our results show that thrombin stimulated the production of ROS and activation of p38 MAPK. ROS were required for thrombin-induced VSMC migration since both generation of ROS and cell migration were significantly attenuated by inhibitors of NAD(P)H oxidase, diphenyleneiodonium (DPI) and apocynin (Apo.), and by the hydrogen peroxide scavenger, catalase (Cat.). Activation of p38 MAPK by thrombin was inhibited by DPI, Apo. and Cat., indicating ROS are used as messengers for activating this kinase. p38 MAPK is an important step since SB 203580, a selective inhibitor of p38 MAPK, suppressed the cell migration induced by thrombin. Furthermore, thrombin increased the expression of vascular endothelial growth factor (VEGF), a chemoattractant for VSMC, and this expression was inhibited by DPI, Apo., Cat. and SB 203580. Addition of anti-VEGF antibody significantly attenuated thrombin-induced migration. Collectively, the data presented here show that thrombin has stimulated VSMC migration and VEGF expression through an ROS-sensitive p38 MAPK pathway. VEGF synthesized and released by the cell served as a secondary mediator in thrombin-directed migration.",
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