Effects of hypoxia-inducible factor-1 signal pathway on proliferation in hypoxic pulmonary artery smooth muscle cells

AIM:To investigate the effect of hypoxia on the proliferation and apoptosis of pulmonary artery smooth muscle cells(PASMC);and to evaluate the role of hypoxia-inducible factor-1α(HIF-1α),iNOS,P-ERK1/2 protein expression in hypoxic pulmonary hypertension(HPH) pathogenesis.METHODS:Cultured rat PASMC were divided into normoxic group;hypoxic group;hypoxia+ADM(adrenomedulin) group,hypoxia+L-NAME(iNOS inhibitor) group;hypoxia+PD98059 group.Proliferation was investigated by MTT and PCNA.Apoptosis was examined by flow-cytometry.Westen blotting was used to measure protein expression of HIF-1α,P-ERK1/2 and iNOS.RESULTS:(1) A value of 24 h-hypoxia was significantly higher than that in the normoxic group(P0.01).In the hypoxia+PD98059 group,ADM was significantly lower than that in hypoxia group,whereas A value of the hypoxia+L-NAME was significantly higher than that in hypoxic group and normoxic group(P0.01).(2) PCNA was positive in PASMC after 24 h hypoxia(P0.01).PD98059,ADM inhibited the expression of PCNA significantly(P0.01),whereas L-NAME increased the expression of PCNA significantly(P0.01).(3) Apoptosis index was not significantly difference among the different groups(P0.05).(4) HIF-1α,iNOS and P-ERK1/2 expression was poorly positive in normoxic group,positive after hypoxia for 4h(P0.01),reaching its peak at 8 h hypoxia(P0.01),HIF-1α,P-ERK1/2 expression declined after 24 h hypoxia.L-NAME promoted the expression of HIF-1α,PD98059 inhibited the expression of HIF-1α,iNOS and P-ERK1/2 partly.ADM inhibited the expression of HIF-1α partly,promoted the expression of iNOS.CONCLUSION:(1) Hypoxia stimulates the proliferation of PASMC,and has no obvious effects on the apoptosis of PASMC.(2) HIF-1 plays an importent role in the proliferation of hypoxic PASMC.