The heat shock protein 70 (Hsp70)/PI3-K/Akt/HIF/biologic pathway as a putative determinant of hypothermic preconditioning in neuroprotection

A number of key players are associated with the neuronal protective response, although a cogent description of how they relate to each other is lacking. In particular, we hypothesize a critical role for heat shock protein 70 (Hsp70) and the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway. Earlier studies show that Hsp70 is dependent on the activation of the PI3-K/Akt pathway and Hsp70 binds to the oxygen-dependent domain (ODD) of hypoxia-inducible factor (HIF) in oxygen deprivation signaling. HIF is the transcription factor for the transcription of genes that encode a number of downstream protective pro-survival factors such as erythropoietin (Epo) and vascular endothelial growth factor (VEGF). We hypothesize, based on the literature to date and preliminary findings from our laboratories, that hypothermic preconditioning of hippocampal neurons induces Hsp70 via PI3-K/Akt activation. This action stabilizes HIF allowing it to accumulate within the cell, ultimately leading to an increase in Epo which contributes to the observed protective effect.We predict that further studies exploring the mechanisms of hypothermic preconditioning are likely to implicate the Hsp70/PI3-K/Akt pathway as a determinant of stabilization leading to a significant increase of HIF-1α and Epo allowing for greater protection of a cell under certain external stressors.