G

Ubiquitination

Nucleus

m-RNA

Nucleus m-RNA

Figure 22. Schematic of proteosome dependent degradation of HIF-la. Normoxia enhances HIF-la degradation and hypoxia prevents it. Hydroxylation by oxygen sensing enzymes (PHD2) and ubiquitination by a E3-ubiquitin ligase complex containing the von Hippel Lindau protein (pVHL) are critical steps of HIF-la degradation process. See text for a more detailed explanation.

A potential cardioprotective role of HIF-la has been demonstrated in mice heterozygous for a knockout allele at the locus encoding HIF-la (HIFla+/-). Intermittent hypoxia resulted in protection of the isolated rat hearts against ischemia and reperfusion injury, in wild type and not in HIFla+/- animals.170

2.4.2 Heat shock factor- Heat shock proteins

The heat shock response is a highly conserved defense mechanism against tissue and cell stress injury. This system represents an endogenous mechanism which antagonizes protein unfolding or misfolding that occurs during stress. It requires heat shock transcription factors (HSF) which phosphorylate and bind heat shock elements within the promoter regions of heat shock protein genes. Figure 24. HSF1 appears to be the primary mediator of the heat shock response system and is activated by ischemia and reperfusion. Activation is triggered by low energy levels, acidosis, alterations in redox state and by increased concentration of unfolded proteins, reviewed by Chi.171

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