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

p38 mitogen-activated protein kinase (MAPK) is involved in intracellular signals that regulate a variety of cellular responses during inflammation. However, the role of p38 MAPK in atherosclerosis, a chronic inflammatory disorder, remains uncertain. The aim of the present study was to examine the role of p38 MAPK in the development of neointimal hyperplasia in balloon-injured rat carotid arteries. Immunohistochemical studies indicated that p38 MARK was rapidly activated in the majority of medial cells in injured arterial 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 than the untreated controls at 14 days after balloon injury (P<0.05). The percentage of proliferating nuclear antigen-positive cells in the media at 48 hours was significantly lower in the FR167653-treated group than in the control group. Quantitative competitive reverse transcription-polymerase chain reaction analysis revealed that interleukin-1 mRNA expression in arteries was significantly inhibited by FR167653 (to 18.1% of control, P<0.05) at 8 hours after balloon injury. Moreover, p38 MAPK activation and interleukin-1 production by lipopolysaccharide-stimulated vascular smooth muscle 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 after percutaneous transluminal coronary angioplasty.