Mitochondria nitric oxide synthase in inflammation and septic shock

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Mitochondria nitric oxide synthase in
inflammation and septic shock
Tu jie
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Nitric Oxide a ubiquitous signaling molecule

• Chemical characters
• 2NOO2 ? 2NO2
• NO2 NO2 ? N2O4
• NO2 NO ? N2O3
• NO OH- ? HNO2 ? NO -2 H
• NO -2 NO H2O ? 2NO -2 2H
• NO -3 NO H2O ? NO -2 NO -3
  2H

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Biosynthesis of Nitric Oxide

H2N
H2N
N-OH
NH2
NOS
NH
NH
NO
NADPH BH4 O2 HEME Ca2/CaM
H3N
COO-
H3N
COO-
L-arginine
L-citrulline
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Three isoforms of NOS
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Cellular and mitochondrial production of NO

• A fourth type of NOS mitochondrial NOS (mtNOS)
• 1. first observed in rat liver mitochondria by
  Ghafourifar group and Giulivi group, 1997-1998
• 2. localize in the mitochondrial innermembrane

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• 3. mtNOS activity is substantial and modulated by
  calcium
• 4. mtNOS continously controls mitochondrial
  respiration

Respiration of IM is markedly inhibited when
mtNOS is stimulated (trace b vs trace a)
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The role of mtNOS in inflammation and septic shock

• Inflammation and septic shock
• A combination of three clinical signs
• vasodilation, hyperthermia, edema
• Myochondrial dysfunction

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• NO production in inflammation and septic shock
• milestone recognition of NO production by
  activated macrophages as part of the inflammatory
  process

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• The impairment by high NO concentration in septic
  shock
• To impair mitochondrial and cellular oxygen
  uptake with
• a simultaneous decrease in the rate of ATP
  synthesis
• To shift the main mitochondrial O2?- metabolic
  route
• (form peroxynitrite (ONOO-), an oxidizing free
  radical that can cause DNA fragmentation and
  lipid oxidation)

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• Cyclosporin A (CsA) in ameliorating
  endotoxin-caused myocardial dysfunction and
  apoptosis in rats (Fauvel H, Marchetti P, Obert G
  , et al. Protective effects of cyclosporin A from
  endotoxin-induced myocardial dysfunction and
  apoptosis in rats J Am J Respir Crit Care Med,
  2002 ,165(4)449-55)

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Conclusion

• Mitochondrial played a central role in the
  intracellular event associated with inflammation
  and septic shock
• The contributions of mtNOS and NOS cytosolic
  isoforms to the total production of NO constitute
  an open and challenging question

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