Sustained activation of p38 MAPK and MMP2 and 9 exacerbate neointima formation following vascular injury in metabolic syndrome rats

Abstract

Following percutanous transluminal coronary angioplasty (PTCA) restenosis is markedly increased in metabolic syndrome patients. We hypothesized that increased restenosis in the metabolic syndrome was due to enhanced activation of p38 MAPK (p38) and subsequent p38‐dependent activation of MMP2 and 9. Carotid arteries were injured with a Fogarty 2F catheter in a rat model mimicking the human metabolic syndrome (JCR rat) and normal, healthy controls (SD rats) and neointima formation was quantified. p38 phosphorylation and MMP2 and 9 expression were assessed by immunoblotting and MMP2 and 9 activity by zymography in injured and contralateral control carotids at 4, 7, 10 and 14 days post injury. No basal differences were observed between JCR and SD rats. Maximal increase in p38 activation of similar magnitude occurred at 4 days post injury in both rat phenotypes. p38 activation rapidly returned to baseline in SD but remained sustained in JCR rats. MMP2 and 9 expression and activation mirrored that of p38. Thus, while the absolute magnitude of activation in response to vascular injury is similar, our findings suggest that the sustained activation of p38 and MMP2 and 9 in the metabolic syndrome contribute to increased neointima formation and may provide targets for pharmacological therapies devised for prevention of restenosis following PTCA. Support: NIH HL 084159 and HL 093052