Role of p38 mitogen-activated protein kinase in neointimal hyperplasia after vascular injury

p38 mitogen-activated protein kinase (MAPK) is involved in intracellular si gnals that regulate a variety of cellular responses during inflammation. Ho wever, the role of p38 MAPK in atherosclerosis, a chronic inflammatory diso rder, remains uncertain. The aim of the present study was to examine the ro le of p38 MAPK in the development of neointimal hyperplasia in balloon-inju red rat carotid arteries. Immunohistochemical studies indicated that p38 MA RK was rapidly activated in the majority of medial cells in injured arteria l walls. Rats treated with FR167653, a selective inhibitor of p38 MAPK, at a dosage of 10 mg.kg(-1).d(-1), had a 29.4% lower intima-to-media ratio tha n the untreated controls at 14 days after balloon injury (P<0.05). The perc entage of proliferating nuclear antigen-positive cells in the media at 48 h ours was significantly lower in the FR167653-treated group than in the cont rol group. Quantitative competitive reverse transcription-polymerase chain reaction analysis revealed that interleukin-1<beta> mRNA expression in arte ries was significantly inhibited by FR167653 (to 18.1% of control, P<0.05) at 8 hours after balloon injury. Moreover, p38 MAPK activation and interleu kin-1<beta> production by lipopolysaccharide-stimulated vascular smooth mus cle cells were inhibited by FR167653 in a concentration-dependent manner in vitro. These results indicate that p38 MAPK is activated in vascular walls after injury and promotes neointimal formation and suggest that selective inhibition of p38 MARK may be effective in the prevention of restenosis aft er percutaneous transluminal coronary angioplasty.