Circulation Research. 2001
Published online before print May 24, 2001, doi: 10.1161/hh1101.091267
Published online before print May 24, 2001, doi: 10.1161/hh1101.091267
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© 2001 American Heart Association, Inc.
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Gene Transfer of Dominant-Negative Mutants of Extracellular Signal–Regulated Kinase and c-Jun NH2-Terminal Kinase Prevents Neointimal Formation in Balloon-Injured Rat Artery
From the Department of Pharmacology (Y.I., S.K., M.N., H.Y., Y.Z., H.I.), Osaka City University Medical School, Osaka; the Gene Experiment Center and Center for Tsukuba Advanced Research Alliance (H.M.), University of Tsukuba; First Department of Internal Medicine (M.H.), Osaka Medical College, Osaka; and Institute for Cellular and Molecular Biology (Y.K.) and Department of Geriatric Medicine (R.M.), Osaka University Medical School, Osaka, Japan.
Correspondence to Shokei Kim, MD, Department of Pharmacology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan. E-mail kims{at}med.osaka-cu.ac.jp
Abstract
Abstract— We previously reported that extracellular signal–regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK), belonging to mitogen-activated protein kinases, are rapidly activated in balloon-injured artery. Therefore, we examined the role of these kinase activations in neointimal formation by using an in vivo gene transfer technique. We made the dominant-negative mutants of ERK (DN-ERK) and JNK (DN-JNK) to specifically inhibit endogenous ERK and JNK activation, respectively. Before balloon injury, these mutants were transfected into rat carotid artery using the hemagglutinating virus of Japan liposome method. In vivo transfection of DN-ERK and DN-JNK significantly suppressed the activation of ERK and JNK, respectively, after balloon injury, confirming successful expression of the transfected genes. Neointimal formation at 14 and 28 days after injury was prevented by gene transfer of DN-ERK or DN-JNK. Furthermore, bromodeoxyuridine labeling index and total cell–counting analysis at 7 days showed that either DN-ERK or DN-JNK remarkably suppressed smooth muscle cell (SMC) proliferation in both the intima and the media after injury. Gene transfer of wild-type ERK (W-ERK) or JNK (W-JNK) significantly enhanced neointimal hyperplasia at 14 days after injury. Furthermore, DN-ERK and DN-JNK significantly suppressed serum-induced SMC proliferation in vitro. We obtained the first evidence that in vivo gene transfer of DN-ERK or DN-JNK prevented neointimal formation in balloon-injured artery by inhibiting SMC proliferation. Thus, ERK and JNK activation triggers SMC proliferation, leading to neointimal formation. These kinases may be the new therapeutic targets for prevention of vascular diseases.
Key Words: balloon • signal transduction • muscle, smooth • remodeling
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