Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:795-801
Published online before print March 13, 2003, doi: 10.1161/01.ATV.0000066132.32063.F2
Published online before print March 13, 2003, doi: 10.1161/01.ATV.0000066132.32063.F2
© 2003 American Heart Association, Inc.
Vascular Biology |
Role of JNK, p38, and ERK in Platelet-Derived Growth Factor–Induced Vascular Proliferation, Migration, and Gene Expression
From the Department of Pharmacology, Osaka City University Medical School, Osaka, Japan, and Gene Experiment Center and Center for Tsukuba Advanced Research Alliance (H.M.), University of Tsukuba, Ibaraki, Japan.
Correspondence to Shokei Kim, MD, Department of Pharmacology, Osaka City University Medical School, Asahimachi, Abeno, Osaka 545-8585, Japan. E-mail kims{at}med.osaka-cu.ac.jp
Objective— We investigated the comparative roles of mitogen-activated protein (MAP) kinases, including c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38, in vascular smooth muscle cell (VSMC) proliferation, migration, and gene expression.
Methods and Results— VSMCs were infected with recombinant adenovirus containing dominant-negative mutants of ERK, p38, and JNK (Ad-DN-ERK, Ad-DN-p38, and Ad-DN-JNK, respectively) to specifically inhibit the respective MAP kinases and then stimulated with platelet-derived growth factor (PDGF)-BB. Ad-DN-ERK attenuated PDGF-BB–induced VSMC proliferation more potently than Ad-DN-p38 or Ad-DN-JNK, indicating the dominant role of ERK in VSMC proliferation. Ad-DN-ERK, Ad-DN-p38, and Ad-DN-JNK similarly inhibited PDGF-induced VSMC migration. Ad-DN-ERK and Ad-DN-JNK suppressed PDGF-BB–induced downregulation of cyclin-dependent kinase inhibitor p27Kip1, whereas Ad-DN-p38 decreased PDGF-BB–induced upregulation of p21Cip1. Ad-DN-ERK inhibited PDGF-BB–induced plasminogen activator inhibitor type-1 (PAI-1), monocyte chemoattractant protein-1, and transforming growth factor-ß1 expressions, Ad-DN-p38 blocked monocyte chemoattractant protein-1 and transforming growth factor-ß1 expression but not PAI-1, whereas Ad-DN-JNK suppressed only PAI-1 expression. Moreover, in vivo gene transfer of Ad-DN-p38 to rat carotid artery caused the inhibition of intimal hyperplasia by balloon injury, indicating the involvement of p38 in vascular remodeling in vivo.
Conclusions— We propose that these 3 MAP kinases participate in vascular diseases via differential molecular mechanisms and are new therapeutic targets for treatment of vascular diseases.
Key Words: platelet-derived growth factor • gene transfer • vascular smooth muscle cell • proliferation • gene expression
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