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(Circulation. 2008;118:658-666.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Requirement for p38 Mitogen-Activated Protein Kinase Activity in Neointima Formation After Vascular Injury

Brandon M. Proctor, PhD; Xiaohua Jin, MD; Traian S. Lupu, DVM; Louis J. Muglia, MD, PhD; Clay F. Semenkovich, MD; Anthony J. Muslin, MD

From the Center for Cardiovascular Research, Department of Medicine (B.M.P., X.J., T.S.L., A.J.M.), Department of Cell Biology and Physiology (B.M.P., X.J., T.S.L., A.J.M.), Department of Pediatrics (L.J.M.), and Division of Endocrinology, Metabolism, and Lipid Research (C.F.S.), Washington University in St Louis, School of Medicine, St Louis, Mo.

Correspondence to Dr Anthony J. Muslin, Box 8086, 660 S Euclid Ave, St Louis, MO 63110. E-mail amuslin{at}imgate.wustl.edu

Received August 17, 2008; accepted May 28, 2008.

Background— Angioplasty and stent delivery are performed to treat atherosclerotic vascular disease but often cause deleterious neointimal lesion formation. Previously, growth factor receptor-bound protein 2 (Grb2), an intracellular linker protein, was shown to be essential for neointima formation and for p38 mitogen-activated protein kinase (MAPK) activation in vascular smooth muscle cells (SMCs). In this study, the role of vascular SMC p38 MAPK in neointimal development was examined.

Methods and Results— Compound transgenic mice were generated with doxycycline-inducible SMC-specific expression of dominant-negative p38 MAPK (DN-p38). Doxycycline treatment resulted in the expression of DN-p38 mRNA and protein in transgenic arteries. Doxycycline-treated compound transgenic mice were resistant to neointima formation 21 days after carotid injury and showed reduced arterial p38 MAPK activation. To explore the mechanism by which p38 MAPK promotes neointima formation, an in vitro SMC culture system was used. Inhibition of p38 MAPK in cultured SMCs by treatment with SB202190 or small interfering RNA blocked platelet-derived growth factor–induced SMC proliferation, DNA replication, phosphorylation of the retinoblastoma protein, and induction of minichromosome maintenance protein 6.

Conclusions— SMC p38 MAPK activation is required for neointima formation, perhaps because of its ability to promote retinoblastoma protein phosphorylation and minichromosome maintenance protein 6 expression.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 118: 607-608. [Extract] [Full Text]