Disease relevance of Epas1

• EPAS1 trans-activation during hypoxia requires p42/p44 MAPK [1].
• Here we report that, in rat pheochromocytoma PC12 cells, nerve growth factor (NGF) stimulation results in a decrease of both basal and hypoxia-induced levels of HIF-2 alpha protein [2].
• The expression of adrenomedullin (AM) mRNA, which is also upregulated by IL-1beta, was dramatically increased in cardiac myocytes transduced with adenovirus expressing EPAS1 [3].

High impact information on Epas1

• Interestingly, NGF effect was specific for HIF-2 alpha mRNA because it did not affect HIF-1 alpha mRNA levels [2].
• Thus, in contrast to the response to hypoxia, the effect of NGF on HIF-2 alpha protein levels is not mediated by the HIF hydroxilases [2].
• Hence, in PC12 cells the level of HIF-2 alpha protein and its effect on gene expression can be down-regulated by stimuli other than oxygen [2].
• NGF treatment reduced HIF-2 alpha mRNA levels even in the presence of actinomycin D, suggesting an effect on mRNA stability [2].
• However, pretreatment with PD98059 had no effect on EPAS1 phosphorylation during hypoxia, suggesting that MAPK targets other proteins that are critical for the trans-activation of EPAS1 [1].

Chemical compound and disease context of Epas1

• HIF-1 alpha and HLF/EPAS are two basic helix-loop-helix/PAS domain transcription factors that bind to hypoxia sensitive elements in the promoters /enhancers of hypoxia sensitive genes such as vascular endothelial growth factor (VEGF) [4].

Biological context of Epas1

• Transient transfection assays using the site-specific mutation of the AM promoter showed that EPAS1 overexpression increases the transcriptional activity through a sequence similar to the consensus HRE (hypoxia responsive element) [3].
• Since IL-1beta has been implicated in the pathogenesis of heart failure and AM can ameliorate the cardiac function, our results suggest that EPAS1 plays a role in the adaptation of the cardiac myocytes during heart failure as well as in the regulation of gene expression by hypoxia [3].
• Deletion analysis and the use of single site reporter constructs demonstrate that sites II and IV are highly responsive to transactivation by DBP and HLF [5].
• The proteins binding to site IV are elevated in this line, suggesting that upregulation of DBP expression in response to inappropriate HLF activity may be mediated through this site [5].

Anatomical context of Epas1

• Here we show that EPAS1 is phosphorylated when PC12 cells are exposed to hypoxia and that p42/p44 MAPK is a critical mediator of EPAS1 activation [1].

Associations of Epas1 with chemical compounds

• NGF treatment did not increase HIF-hydroxylase gene expression or activity, and the reduction of the HIF-2 alpha protein level upon stimulation was observed even in the presence of HIF-hydroxylase inhibitors such as deferoxamine or dimethyloxoglutarate [2].
• Cardiac expressions of HIF-1 alpha and HLF/EPAS, two basic loop helix/PAS domain transcription factors involved in adaptative responses to hypoxic stresses [4].
• These compounds are 5'-methylethyl(5'adenosyl) sulfonium chloride (MEAS), 5'-methylpropyl-(5'adenosyl)sulfonium chloride (MPAS), and 5'-ethylpropyl(5'-adenosyl)sulfonium chloride (EPAS) They were prepared by reacting an alkyl iodide with the appropriate alkyladenosyl thioether [6].
• Such an induction of EPAS1 by IL-1beta was efficiently inhibited by the pretreatment of the cells with Src kinase inhibitors, such as herbimycin A and PP1 [3].
• The isolated rat heart subjected to HLF was used as model of global ischaemia, and sarcolemmal permeability assessed by release of LDH from and influx of lanthanum and Ca2+ into myocardial tissue [7].

Other interactions of Epas1

• To date, virtually nothing is known about the signaling pathways that lead to either EPAS1 or HIF1-alpha activation [1].
• We further show that hypoxia-induced trans-activation of EPAS1 is independent of Ras [1].

Analytical, diagnostic and therapeutic context of Epas1

• Mechanical function as well as tissue high energy phosphates were significantly depressed during both HLF and reperfusion [7].
• Palmitate (0.5 mM conjugated to 0.1 mM albumin) or substrate-free perfusion caused ultrastructural damage and loss of normal sarcolemmal integrity during both normoxia and HLF [7].

References