Hypoxia-Induced Mitogenic Factor Mediated Hypoxic Pulmonary Hypertension Of Rat Viaactivated PI3K/Akt/mTOR And PKC/MAPKs Pathways

[Objectives]:We investigated the expression of hypoxia induced mitogenic factor and the phosphorylation of PI3K/Akt/m TOR and PKC/MAPKs pathways within different time courses in chronic hypoxia induced pulmonary artery hypertension.Moreover,by suppressing and overexpressing HIMF in pulmonary of rats,we explored its role in hypoxic pulmonary artery smooth muscle proliferation and the mechanism of PI3K/Akt/m TOR and PKC/MAPKs signaling pathways involved in the process,to provide a novel possible therapy for hypoxic pulmonary hypertension.[Methods]: We induced pulmonary artery hypertension via chronic hypoxia exposure,rats in chronic-hypoxia exposure had been given lentivirus or recombinant HIMF protein intratracheally to silence or upregulate HIMF during chronic hypoxia.We measured mean pulmonary artery pressure right ventricular hypertrophy index,vascular remodeling in time courses.Western-blot,RT-PCR,immunohistochemistry to exame the different time points of HIMF,p-PI3K(p85),p-Akt(Ser473),p-m TOR,p-PKC,p-P44/42(Thr202/Tyr204)expression.[Results]: Part one: The m PAP increased obviously(21.51± 3.462)mm Hg after hypoxia for 7 days,reaching its peak after hypoxia for 14 days,then it maintained at a high level thereafter.The right ventricular hypertrophy index began to appear at 14 days after hypoxia(P< 0.05),and reached the peak for hypoxia for 21 days.The pulmonary vascular remodeling was seen after hypoxia for 7 days.The level of HIMF protein and m RNA in pulmonary artery and pulmonary artery smooth muscle cells reached the peak after hypoxia for 3 days;with the prolonged hypoxia,the protein and m RNA of HIMF decreased gradually.And the expression of p-PI3K(p85),p-Akt(Ser473),p-m TOR,p-PKC,p-P44/42(Thr202/Tyr204)increased gradually during the chronic hypoxia time courses.Part two: The expression of HIMF m RNA and protein induced by chronic hypoxia in pulmonary artery smooth muscle cells and pulmonary artery decreased with HIMF silenced(P< 0.05).The m PAP,RVHI and pulmonary vascular remodeling also declined(P< 0.05)for silenced HIMF,with the same tendency of p-PI3K(p85),p-Akt(Ser473),p-m TOR,p-PKC,p-P44/42(Thr202/Tyr204)(P < 0.05).Part three: The expression of HIMF m RNA and protein induced by chronic hypoxia in pulmonary artery smooth muscle cells and pulmonary artery upregulated with HIMF protein overexpressed(P< 0.05).The m PAP,RVHI and also enhanced(P<0.05)for useage of recombinant HIMF protein,and the espression of p-PI3K(p85),p-Akt(Ser473)and p-PKC also upregulated.To our surprise,the expression of p-m TOR and p-P44/42(Thr202/Tyr204)had not markedly increased,and the pulmonary vascular remodeling also had not futher increased.[Conclusion]:Hypoxia upregulate rats pulmonary artery HIMF,to activate PI3K/Akt/m TOR and PKC/MAPK signal pathways,increasing the mean pulmonary artery pressure and right ventricular hypertrophy index,promoting pulmonary vascular remodeling,thus develop into hypoxic pulmonary hypertension.