Hydrogen sulfide in cardiac hypoxia: regulation of cystathioninelyase

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Hydrogen sulfide in cardiac hypoxia regulation
of cystathionine-?-lyase

• Sean Bryan
• MSc. (Biology) Candidate
• Department of Biology, Lakehead University

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Gasotransmitters

• small gas molecules
• freely permeable to membranes
• endogenously produced, enzymatically regulated
• specific functions at physiologically relevant
  conc.

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H2S An unlikely hero

• noxious history
• rotten egg gasbroad spectrum toxicant CDN
  industry
• endogenous production
• synthesis by CBS, CSE enzymes physiological
  concentrations
• numerous biological effects throughout body
• brain, vasculature, heart, pancreas, lungs, etc.

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H2Ss cardioprotective actions

• preserves mitochondrial structure/function
• decreases contractility
• slows metabolism
• antioxidant
• anti-inflammatory
• anti-hypertrophic

Lefer (PNAS) 2007
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Experimental overview

• Hypothesis Endogenous H2S is implicated in the
  
• hypoxic stress response
  in cardiomyocytes

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CSE increased in hypoxia/reoxygenation

• CSE protein expression increased in H/R
• effect of CSE inhibitor
• no change in ROS

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CSE increased in hypoxia/reoxygenation

• CSE protein expression increased in H/R
• effect of CSE inhibitor
• no change in ROS
• abrogated increase in membrane potential
• increased cell death

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CSE increased in hypoxia/reoxygenation

• CSE protein expression increased in H/R
• effect of CSE inhibitor
• no change in ROS
• abrogated increase in membrane potential
• increased cell death

suggests CSE-mediated cardioprotection
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CSE increased in cobalt-induced signaling

• cobalt chloride (CoCl2) induces HIF-1a signaling
• disparity in ROS level and cell death at 24h

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CSE increased in cobalt-induced signaling

• cobalt chloride (CoCl2) induces HIF-1a signaling
• disparity in ROS level and cell death at 24h
• variable CSE protein expression pattern noted

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CSE increased in cobalt-induced signaling

• cobalt chloride (CoCl2) induces HIF-1a signaling
• disparity in ROS level and cell death at 24h
• variable CSE protein expression pattern noted

• CSE is upregulated in both hypoxia models
• CSE may be a downstream target of HIF-1a

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Current work future directions

• confirm presumed H2S increase with CSE expression
• use chemical inhibitors to discern relationship
  of CSE and HIF-1a
• siRNA knockdown of CSE characterization of redox
  and inflammatory markers

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Acknowledgements

• Dr. Neelam Khaper (NOSM)
• Dr. Rui Wang (Lakehead)
• Dr. Guangdong Yang (Lakehead)
• Ms. Mi-Sung Yim (Lakehead)
• Mr. Lee Shewchuk (NOSM)