HIF activation

Weidemann A, Bernhardt WM, Klanke B, Daniel C, BuchholzB,CampeanV, Amann K,WarneckeC,WiesenerMS, Eckardt KU,and Wiliam C. HIF activation protects from acute kidney injury. J Am Soc Nephrol 19 486-494,2008. 

Downstream effects of HIF activation include modulation of glycolysis capacity ( Warburg effect ), cell survival, and increased angiogenesis. 

Glover, L.E., Irizarry, K., Scully, M., Camphell, E.L., Bowers, B.E., Aheme, C.M., and Colgan, S.P. 2011. IFN-y attenuates hypoxia-inducihle factor (HIF) activity in intestinal epithelial cells... 

Figure 1 Role of prolyl hydroxylases as an oxygen-sensor regulating HIF activation. In the presence of oxygen, PHD enzymes convert specific prolyl residues in HIF-a chains to hydroxyproline. The enzymes require iron as a cofactor. Modified HIF-a chains are captured hy the pVHL ubiquitin E3 ligase complex, ubiquitylated, and destroyed by the proteasome. Under reduced oxygenation, HIF-a rapidly accumulates, enters the nucleus, dimerizes with a jS subunit, recruits coactivators, and activates transcription of genes with hypoxic response elements (HRE). HYP, hydroxyproline.

Thus, current studies focus on the inhibition of PHDs by small molecular compounds to modulate HIF activity. 

Specific inhibition of PHDl may thus mediate tissue protection through a reduced oxidative stress, independent of HIF activation. Unfortunately, none of the current, thus far reported, PHD inhibitors is specific for a distinct PHD subtype. ... 

Wang X, Li C, Chen Y, Hao Y, Zhou W, Chen C, Yu Z (2008) Hypoxia enhances CXCR4 expression favoring microglia migration via HIF-1 alpha activation. Biochem Biophys Res Commun 371 283-288... 

Dihydroxybenzoic acid (DHB) is also a commonly used tool to measure the pharmacological effects of HIF-la stabilization via PHD inhibition. Recently, it was shown that mice pretreated with DHB (100 mg/kg, i.p.) showed a marked resistance to the neurotoxic effects of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) via protection of dopaminergic cell loss and striatal denervation. Importantly, this protection was seen to coincide with HIF-la stabilization, and the prevention of the MPTP-induced loss of ferroportin and striatal iron. Additionally, in these studies, DHB was also observed to block MPTP-induced reduction in mitochondrial pyruvate dehydrogenase, at both the mRNA level and through the measurement of enzyme activity in midbrain substantia nigra [26]. 

It is well known that 1,10-phenanthrolines are highly active ironchelating agents. The parent compound itself has recently been shown to increase HIF-la levels in ocular tissue and to suppress 02-mediated epithelial cell proliferation when administered to mice [29]. A quantitative assay was developed to measure transcriptional potency of certain HIF stabilizers via an HRE-mediated (3-lactamase production in which the EC50 of 1,10-phenanthroline was measured to be approximately 8 pM. In addition, VEGF was dose-dependently produced in mouse embryonic fibroblasts by 1,10-phenanthroline with an EC50 of... 

NF-kB AP-1 Spl, Egr-1 (zinc finger TFs) VDR, RXR (nuclear hormone R) PPARy NFAT HSFs p53 HIF-1 -activation in resting cells, low level RNI -inhibition in stimulated cells, high level RNI -activation in unstimulated cells, low level RNI -inhibition in activated cells -rather uniform inhibition -activation if Spl de-represses the e.g. TNFa promoter -inhibition of DNA-binding and reporter activity -activation at low level RNI -inhibition at high level RN I —inhibition in activated N K cells -activation (HSP70 expression) —activation (for details see below) -activation under normoxia (for details see below) -inhibition under hypoxia... 

TF transcription factor, R receptor, Fur ferric uptake regulation protein, NF-kB nuclear factor-kB, AP-1 activator protein-1, Egr-1 early growth response-1, VDR la,25-dihydroxy-vitamin D3 receptor, RXR retinoid X receptor, PPARy peroxisome proliferator-activated receptor y NFAT nuclear factor of activated T-cells, HSF heat shock factor, p53 tumor suppressor p53, HIF-1 hypoxia inducible factor-1. ... 

As proposed schematically in Fig. 13.2, RNI may block PHD-activity, attenuate proline hydroxylation of HIF-la, dissociate HIF-la from pVHL with the consequence of protein stabilization based on decreased proteasomal degradation. 

Fig. 13.2 Stability regulation of HIF-la and as well as FIH activity under normoxia, thus...

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