Requirement for p38 mitogen-activated protein kinase activity in neointima formation after vascular injury.
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 p38alpha MAPK in neointimal development was examined.


RESULTS
Compound transgenic mice were generated with doxycycline-inducible SMC-specific expression of dominant-negative p38alpha MAPK (DN-p38alpha). Doxycycline treatment resulted in the expression of DN-p38alpha 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 p38alpha MAPK promotes neointima formation, an in vitro SMC culture system was used. Inhibition of p38alpha 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 p38alpha MAPK activation is required for neointima formation, perhaps because of its ability to promote retinoblastoma protein phosphorylation and minichromosome maintenance protein 6 expression.
Proctor
Brandon M
BM
Center for Cardiovascular Research, Department of Medicine, Washington University, St. Louis, School of Medicine, ST. Louis, Mo., USA.
Jin
Xiaohua
X
Lupu
Traian S
TS
Muglia
Louis J
LJ
Semenkovich
Clay F
CF
Muslin
Anthony J
AJ
D017130:Angioplasty / Q000009:adverse effects*; D000818:Animals; D020212:Carotid Artery Injuries / Q000378:metabolism* / Q000628:therapy; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D005260:Female; D015870:Gene Expression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064151:Minichromosome Maintenance Complex Component 6; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000293:injuries; D010766:Phosphorylation; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D017539:Tunica Intima / Q000201:enzymology / Q000293:injuries; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism*
D018797:Cell Cycle Proteins; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D048051:p38 Mitogen-Activated Protein Kinases; C491205:Mcm6 protein, mouse; D064151:Minichromosome Maintenance Complex Component 6