Heat Shock Proteins in the Brain: Role of Hsp70, Hsp 27, and HO-1 (Hsp32) and Their Therapeutic Potential

Abstract

Heat shock proteins are induced by heat shock via HSF proteins binding to heat shock elements in their promoters. Hsp70 is massively induced in response to misfolded proteins following cerebral ischemia in all cell types, but is induced mainly in neurons in the ischemic penumbra. Over expression of Hsp70 via transgenes and viruses or systemic administration of Hsp70 fusion proteins that allow it to cross the blood brain barrier protect brain against ischemia in most reported studies. Hsp27 can exist as unphosphorylated large oligomers that prevent misfolded protein aggregates and improve cell survival. P-Hsp27 small oligomers bind specific protein targets to improve survival. In brain Protein Kinase D phosphorylates Hsp27 following ischemia which then binds ASK1 to prevent MKK4/7, JNK, Jun induced apoptosis and decrease infarct volumes following focal cerebral ischemia. Heme oxygenase-1 (HO-1) metabolizes heme to carbon monoxide, ferrous ion and biliverdin. CO activates cGMP to promote vasodilation, and biliverdin is converted to bilirubin which can serve as an anti-oxidant both of which may contribute to the reported protective role of HO-1 in cerebral ischemia and subarachnoid hemorrhage. However, ferrous ion can react with hydrogen peroxide to produce pro-oxidant hydroxyl radicals which may explain the harmful role of HO-1 in intracerebral hemorrhage. Heat shock proteins as a class have great potential as treatments for cerebrovascular disease and have yet to be tested in the clinic.

Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages

“…The inhibition of Hsp90 activity has been shown to induce increased expression of Hsp70 and Hsp90 via HSF-1 activation and is related to cell protection during stress (Sharp et al, 2013;Paul and Mahanta, 2014;Leung et al, 2015). Accordingly, we observed the induction of Hsp90 expression in LPSstimulated macrophages pretreated with gedunin, 17-AAG, and dexamethasone (which also modulates HSF-1 activity; Knowlton and Sun, 2001) (Supplemental Fig.…”

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“…6,35) Thus, we further investigated the role of HSP70 in the protective effect of Zligustilide against OGD-Reoxy induced injury. The results Recent study demonstrated that overproduction of damaged proteins following focal cerebral ischemia increases protein ubiquitination, resulting in ubiquitinated proteins aggregation.…”

“…4) It's reported that over-expression of HSP70 via transgenes and viruses or systemic administration of HSP70 fusion proteins that allow it to cross the blood brain barrier protects the brain against ischemia, 5,6) suggesting that increasing HSP70 level or activity may be a potential therapeutic target for pharmacological intervention of ischemic diseases.…”

“…3) Heat shock protein 70 (HSP70) is a major inducible heat shock protein that basically functions as a molecular chaperone and plays an important role in preventing protein aggregation, degrading unstable and misfolded proteins and transporting proteins between cellular compartments. 4) It's reported that over-expression of HSP70 via transgenes and viruses or systemic administration of HSP70 fusion proteins that allow it to cross the blood brain barrier protects the brain against ischemia, 5,6) suggesting that increasing HSP70 level or activity may be a potential therapeutic target for pharmacological intervention of ischemic diseases.…”

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