Inhibition of myocardial apoptosis by postconditioning is associated with attenuation of oxidative stress-mediated nuclear factor-κB translocation and TNFα release

Hajime Kin, Ning Ping Wang, James Mykytenko, James Reeves, Jeremiah Deneve, Rong Jiang, Amanda J. Zatta, Robert A. Guyton, Jakob Vinten-Johansen, Zhi Qing Zhao

Research output: Contribution to journalArticle

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Abstract

Oxidative stress-stimulated nuclear factor-κB (NF-κB) activation has been associated with rapid transcription of TNF-α and induction of apoptosis. This study tested the hypothesis that postconditioning (Postcon) reduces myocardial apoptosis and inhibits translocation of NF-κB and release of TNF-α secondary to an attenuation of oxidant generation during reperfusion. Anesthetized rats were subjected to 30 min of ischemia and 3 h of reperfusion and divided randomly to Control or Postcon (three cycles of 10-s reperfusion and 10-s reocclusion applied at the onset of reperfusion) group, respectively. Relative to Control, Postcon reduced the plasma malondialdehyde (1.21 ± 0.08 vs. 0.8 ± 0.06* μM/mL) and decreased the generation of superoxide radical in area at risk myocardium (dihydroethidium staining). Compared with Control, Postcon also inhibited translocation of NF-κB to nuclei (167% ± 21% vs. 142% ± 18%*), decreased the level of plasma TNF-α (1,994 ± 447 vs. 667 ± 130* pg/mL), and inhibited caspase-3 activity (0.57% ± 0.1% vs. 0.21% ± 0.1%*). The number of apoptotic cells (percent total nuclei) in ischemic myocardium was reduced (20% ± 1% vs. 11% ± 2%*), consistent with reduced appearance of DNA fragmentation. To support whether oxidant generation is important in the triggering of cytokine release and apoptosis, N-acetylcysteine (NAC), a potent antioxidant agent, was administered before ischemia and at reperfusion. Treatment with NAC inhibited superoxide radical generation and decreased plasma malondialdehyde to a comparable level to that in Postcon, concomitant with an inhibition of NF-κB expression (42% ± 8%*) and reduction of release of TNF-α (231 ± 72* pg/mL). Caspase-3 activity (0.33% ± 0.1%*) and apoptotic cells (12% ± 1%*) were also comparably reduced by NAC. These data suggest that Postcon attenuates myocardial apoptosis, reduces caspase-3 activity, and is potentially mediated by inhibiting oxidant-activated NF-κB-TNF-α signaling pathway. *P < 0.05 Postcon and NAC vs. Control.

Original languageEnglish (US)
Pages (from-to)761-768
Number of pages8
JournalShock
Volume29
Issue number6
DOIs
StatePublished - Jun 1 2008
Externally publishedYes

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Reperfusion
Acetylcysteine
Oxidative Stress
Apoptosis
Oxidants
Caspase 3
Malondialdehyde
Superoxides
Myocardium
Ischemia
DNA Fragmentation
Cell Count
Antioxidants
Staining and Labeling
Cytokines

All Science Journal Classification (ASJC) codes

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Inhibition of myocardial apoptosis by postconditioning is associated with attenuation of oxidative stress-mediated nuclear factor-κB translocation and TNFα release. / Kin, Hajime; Wang, Ning Ping; Mykytenko, James; Reeves, James; Deneve, Jeremiah; Jiang, Rong; Zatta, Amanda J.; Guyton, Robert A.; Vinten-Johansen, Jakob; Zhao, Zhi Qing.

In: Shock, Vol. 29, No. 6, 01.06.2008, p. 761-768.

Research output: Contribution to journalArticle

Kin, Hajime ; Wang, Ning Ping ; Mykytenko, James ; Reeves, James ; Deneve, Jeremiah ; Jiang, Rong ; Zatta, Amanda J. ; Guyton, Robert A. ; Vinten-Johansen, Jakob ; Zhao, Zhi Qing. / Inhibition of myocardial apoptosis by postconditioning is associated with attenuation of oxidative stress-mediated nuclear factor-κB translocation and TNFα release. In: Shock. 2008 ; Vol. 29, No. 6. pp. 761-768.
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AU - Deneve, Jeremiah

AU - Jiang, Rong

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AU - Vinten-Johansen, Jakob

AU - Zhao, Zhi Qing

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N2 - Oxidative stress-stimulated nuclear factor-κB (NF-κB) activation has been associated with rapid transcription of TNF-α and induction of apoptosis. This study tested the hypothesis that postconditioning (Postcon) reduces myocardial apoptosis and inhibits translocation of NF-κB and release of TNF-α secondary to an attenuation of oxidant generation during reperfusion. Anesthetized rats were subjected to 30 min of ischemia and 3 h of reperfusion and divided randomly to Control or Postcon (three cycles of 10-s reperfusion and 10-s reocclusion applied at the onset of reperfusion) group, respectively. Relative to Control, Postcon reduced the plasma malondialdehyde (1.21 ± 0.08 vs. 0.8 ± 0.06* μM/mL) and decreased the generation of superoxide radical in area at risk myocardium (dihydroethidium staining). Compared with Control, Postcon also inhibited translocation of NF-κB to nuclei (167% ± 21% vs. 142% ± 18%*), decreased the level of plasma TNF-α (1,994 ± 447 vs. 667 ± 130* pg/mL), and inhibited caspase-3 activity (0.57% ± 0.1% vs. 0.21% ± 0.1%*). The number of apoptotic cells (percent total nuclei) in ischemic myocardium was reduced (20% ± 1% vs. 11% ± 2%*), consistent with reduced appearance of DNA fragmentation. To support whether oxidant generation is important in the triggering of cytokine release and apoptosis, N-acetylcysteine (NAC), a potent antioxidant agent, was administered before ischemia and at reperfusion. Treatment with NAC inhibited superoxide radical generation and decreased plasma malondialdehyde to a comparable level to that in Postcon, concomitant with an inhibition of NF-κB expression (42% ± 8%*) and reduction of release of TNF-α (231 ± 72* pg/mL). Caspase-3 activity (0.33% ± 0.1%*) and apoptotic cells (12% ± 1%*) were also comparably reduced by NAC. These data suggest that Postcon attenuates myocardial apoptosis, reduces caspase-3 activity, and is potentially mediated by inhibiting oxidant-activated NF-κB-TNF-α signaling pathway. *P < 0.05 Postcon and NAC vs. Control.

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