Heat shock proteins in the brain: role of Hsp70, Hsp 27, and HO-1 (Hsp32) and their therapeutic potential

Transl Stroke Res. 2013 Dec;4(6):685-92. doi: 10.1007/s12975-013-0271-4. Epub 2013 Aug 3.

Abstract

Heat shock proteins (Hsps) are induced by heat shock via heat shock factor 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. Overexpression 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 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 the brain, protein kinase D phosphorylates Hsp27 following ischemia which then binds apoptosis signal-regulating kinase 1 to prevent MKK4/7, c-Jun NH(2)-terminal kinase, and 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Apoptosis
  • Biliverdine / metabolism
  • Brain Ischemia / metabolism*
  • Carbon Monoxide / metabolism
  • Cerebrum / metabolism*
  • HSP27 Heat-Shock Proteins / metabolism
  • HSP70 Heat-Shock Proteins / metabolism
  • Heat-Shock Proteins / metabolism*
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Neurons / metabolism*
  • Protein Folding
  • Protein Kinases / metabolism
  • Reactive Oxygen Species / metabolism
  • Subarachnoid Hemorrhage / metabolism

Substances

  • HSP27 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Reactive Oxygen Species
  • Carbon Monoxide
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • Protein Kinases
  • Biliverdine