Inhibition of ERK or Akt ameliorates intimal hyperplasia via up-regulation of Cx37 and down-regulation of Cx43 in balloon injury rat model.

Background: Connexins (Cxs) are reported to participate in atherosderosis associated intimal hyperplasia (IH), while their function involved in the balkxm injury (BI) induced IH and restenosis is less reported. Methods: Forty-eight male Sprague-Dawley rats were randomly assigned to not injured (NI) group and BI group, which were further administrated with ERK-inhibitor U0216 and Akt-inhibitor MIK2206. Western blot and RT-PCR were utilized to detect the expression of Cx30, Cx37, Cx40, and Cx43 at 6 hours, 24 hours, 7 days, and 14 days post-surgery. H&F, staining and related intima area, media area, and luminal area measurement were applied to indicate neointima formation and IH. ERK and Akt phosphorylation levels and proliferating cell nuclear antigen (PCNA) immunostaining were also detected. Results: Among the four Cxs detected, Cx37 showed down-regulated, and Cx43 showed up-regulated temporal expression pattern in BI rats with confirmed neointima formation. Up-regulated p-ERK (P<0.01) and p-Akt (P<0.01) can be detected in BI rats compared with NI rats. Meanwhile, U0216 and M1K2206 can significantly reduce Cx43 expression and increase CX37 expression accompanied with reduced neointima formation and PCNA staining (P<0.05 or P<0.01) in BI rats. Conclusions: ERK or Akt inhibition can alleviate BI-induced IH via up-regulation of Cx37 and down-regulation of Cx43.