Erythropoietin mediated expression of Placenta Growth Factor is regulated via activation of hypoxia inducible factor -1{alpha} and post-transcriptionally by mir214 in Sickle Cell Disease

Placental growth factor (PlGF) plays an important role in various pathological conditions and diseases such as inflammation, cancer, atherosclerosis and sickle cell disease (SCD). Abnormally high PlGF levels in SCD patients are associated with increased inflammation and pulmonary hypertension and reactive airway disease; however, the transcriptional and post-transcriptional mechanisms regulating PlGF expression are not well defined. Herein, we show that treatment of human erythroid cells and colony forming units with erythropoietin (EPO) increased PlGF expression. Our studies showed EPO mediated activation of HIF-1α led to subsequent binding of HIF-1α to hypoxia response elements (HREs) within the PlGF promoter, as demonstrated by luciferase transcription reporter assays and ChIP analysis of the endogenous gene. Additionally, we showed miR214 post-transcriptionally regulated the expression of PlGF as demonstrated by luciferase reporter assays using wild-type and mutant PlGF-3’UTR constructs. Furthermore, synthesis of miR214, located in an intron of DNM3, was transcriptionally regulated by transcription factors, PPARα and HIF-1α. These results were corroborated in vivo wherein plasma from SCD patients and lung tissues from sickle mice showed an inverse correlation between PlGF and miR214 levels. Finally, we observed that miR214 expression could be induced by fenofibrate, an FDA approved PPARα agonist, thus revealing a potential therape...
Source: BJ Disease - Category: Biochemistry Authors: Tags: BJ Disease Source Type: research