Role of heme oxygenase in the protection afforded skeletal muscle during ischemic tolerance

Alison A. Dungey, Amit Badhwar, Aurelia Bihari, Peter R. Kvietys, Kenneth A. Harris, Thomas L. Forbes, Richard F. Potter

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Objective: Ischemic tolerance (IT) is known to improve resistance to ischemia/reperfusion (I/R)-induced injury; however, the mechanisms remain unknown. The authors hypothesized that induction of heme oxygenase (HO), a heat shock protein, would provide anti-inflammatory benefits during IT, thereby preventing leukocyte-derived I/R injury. Methods: Male Wistar rats were randomly assigned to sham (n = 4), I/R (n = 9), preconditioning (PC)+I/R (n = 7), chromium mesoporphyrrin, to inhibit HO (CrMP; n = 4), or PC+I/R+CrMP (n = 6) groups. PC consisted of 5 cycles of I/R, each lasting 10 min, induced by tightening a tourniquet placed above the greater trochantor of the hindlimb. Twenty-four hours later, the hindlimb underwent 2 h of no-flow ischemia followed by intravital microscopy during 90 min reperfusion to assess capillary perfusion (#/mm), tissue injury (ratio of ethidium bromide to bisbenzimide labeled cells/100 μm2), leukocyte rolling (Lr, #/1000 μm2), and adhesion (La, #/1000 μm2) in postcapillary venules of the extensor digitorum longus (EDL) muscle. Results: In the I/R group, Lr was significantly in creased (7.1 ± 0.4) compared to sham (3.1 ± 0.4). PC+I/R increased Lr (10.8 ± 0.72), which was further exacerbated by the removal of HO (14.2 ± 1.3). La (7.8 ± 2.0) was significantly increased compared to sham (2.4 ± 0.9), while PC returned La back to sham levels (1.9 ± 0.7). Removal of HO activity, via CrMP, had no significant effect on La (3.9 ± 0.7). However, CrMP removed the protection to microvascular perfusion (I/R = 9.4 ± 1.1, PC = 16.6 ± 1.8, sham = 20.5 ± 2.8, PC+CrMP+I/R = 12.3 ± 2.3) and prevented protection from ischemia-induced tissue injury. Conclusion: The data suggest that HO is an important protective mechanism during IT in skeletal muscle, but such protection was by mechanisms other than altered leukocyte-endothelial cell interaction.

Original languageEnglish
Pages (from-to)71-79
Number of pages9
JournalMicrocirculation
Volume13
Issue number2
DOIs
StatePublished - Mar 2006
Externally publishedYes

Keywords

  • Heme oxygenase
  • Inflammation
  • Ischemic tolerance
  • Preconditioning
  • Skeletal muscle

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