Fig. 3
The transcriptional and posttranscriptional influence of hypoxia on NOS3 mRNA levels. During hypoxia, HIF-1 and HIF-2 accumulate in the nucleus, where they bind to a sequence in the promoter region of NOS3 termed the hypoxia-response element (HRE), and in doing so, induce NOS3 expression. Hypoxia disrupts hnRNP E1/NOS3 3′-UTR interactions and makes this transcript susceptible to sONE and miRNA-related down-regulation. HIF-1 induces miR-155 that along with miR-765 and miR-24 destabilizes NOS3 mRNA. Furthermore, during hypoxia, miR-214 has negative effect on NOS3 expression. Hypoxia is accompanied by deregulation of ER homeostasis and HIF-1-related activation of the ER stress response. The proadaptive and proangiogenic ER stress transcription factor sXBP1 stimulates NOS3 expression transcriptionally and postranscriptionally through reduction of miR-24, miR-125 and miR-214. However, another proapoptotic ER stress transcription factor, CHOP, binds to the 5′UTR and represses transcription. The hypoxamiRs also modulate Act signaling pathway and consequently eNOS activity. During hypoxia, the changes in the expression levels of miR-155, miR-101, miR-486, miR-21 and miR-126 stimulate Akt activation, whereas miR-26 prevents Act signaling. The (+) expression profile changed during hypoxia contributes to increased expression and activity of NOS3; the (-) expression profile changed during hypoxia has a negative effect on the expression and activity of NOS3; (¥) depicts indirect effects on the NOS3 gene