Role of HSP60 in Myocardial Apoptosis

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Role of HSP60 in Myocardial Apoptosis
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Heat Shock Proteins

• Highly conserved proteins in all pro- and
  eukaryotic cells
• Expressed as intracellular response to stress
  which includes ischemia, hypoxia, ATP depletion
  and free radicals
• Accumulation of heat shock proteins in cardiac
  cells enhances myocardial resistance to
  ischemia/reperfusion injury and improves
  post-ischemic recovery of cardiac function

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Heat Shock Protein 60

• HSP60 is constitutively expressed in the
  cytoplasm and is translocated to mitochondria
• HSP60 promotes folding of many proteins imported
  into the mitochondrial matrix and maintain normal
  mitochondrial function
• HSP60 plays a role in protecting cells against
  injury and has a role in cardioprotection
• About 65-75 of HSP60 is mitochondrial, whereas
  25-35 is extramitochondrial

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Hsp60
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Role of HSP60 as intracellular molecules
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Decreased expression of HSP60 induces apoptosis
Levels of HSP60 after antisense treatment
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Cardiomyocytes viability after AS treatment
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Cytochrome c release and caspase-3 activation
after antisense treatment
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Levels of bax, bak and Bcl-2 after AS treatment
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HSP60 , Hypoxia and Apoptosis

• Adult rat myocytes were studied at end-hypoxia
  and at 10 and 24h of reoxygenation
• HSP60 levels were unchanged at end hypoxia and
  decreased 33 and 40 at 10 and 24h of
  reoxygenation
• Mitochondrial HSP60 was unchanged while cytosolic
  HSP60 translocates to the plasma membrane
• In cytosol in the absence of HSP60, bax moves to
  the mitochondria and causes cytochrome c release
  and apoptosis

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HSP60 levels during hypoxia/reoxygenation
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Cyt c release during hyp/reox
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Bax levels during hyp/reox
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Bcl-2 levels during hyp/reox
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HSP 60 and bax localization in cytosol and
org/memb after hypoxia
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Distribution of HSP60 and bax in plasma membrane
and mitochondria after hypoxia
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Co-localization of Bax With HSP60
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PLASMA MEMBRANE
HSP60
BAX
STRESS
CYTC
CYTC
HSP60
HSP60
MITOCHONDRION
CYTOPLASM
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Extracellular HSP60
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HSP60 as an inducer of Inflammation
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Binding of HSP60 to cardiomyocytes
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Role of HSP60 in Plasma Membrane
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Release of Cytokines by HSP60
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Identification of post-translational
modifications of HSP60
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Glycosylation of extracellular HSP60
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Extracellular HSP60 and Apoptosis
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Conclusions

• Endogenous HSP60 acts as a protector of the cell
  by stabilizing macromolecules
• Intracellular HSP60 is antiapoptotic as it binds
  with proapoptotic bax
• Extracellular HSP60 induces apoptosis

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Future Directions

• What is the regulation and function of movement
  of HSP60 to the plasma membrane?
• Is HSP60 a ligand for TLR4 on the membrane?
• Is membrane HSP60 released?
• Do post-translational modifications alter the
  toxicity of exogenous HSP60?