Aldose reductase is an obligatory mediator of the late phase of ischemic preconditioning

Ken Shinmura, Roberto Bolli, Si Qi Liu, Xian Liang Tang, Eitaro Kodani, Yu ting Xuan, Sanjay Srivastava, Aruni Bhatnagar

Research output: Contribution to journalArticle

Abstract

Aldose reductase (AR), a member of the aldo-keto reductase superfamily, has been shown to metabolize toxic aldehydes generated by lipid peroxidation, suggesting that it may serve as an antioxidant defense. To investigate its role in the late phase of ischemic preconditioning (PC), conscious rabbits underwent 6 cycles of 4-minute coronary occlusion/4-minute reperfusion. Twenty-four hours later, there was a marked increase in AR protein and activity and in the myocardial content of sorbitol, a unique product of AR catalysis. Pretreatment with Nω-nitro-L-arginine, a nitric oxide synthase inhibitor, or chelerythrine, a protein kinase C inhibitor (both given at doses that block late PC in this model), prevented the increase in AR protein 24 hours later, demonstrating that ischemic PC upregulates AR via nitric oxide- and protein kinase C-dependent signaling pathways. The AR-selective inhibitors tolrestat and sorbinil prevented AR-mediated accumulation of sorbitol and abrogated the infarct-sparing effect of late PC, demonstrating that enhanced AR activity is necessary for this cardioprotective phenomenon to occur. Inhibition of AR did not affect infarct size or the myocardial accumulation of the lipid peroxidation product 4-hydroxy trans-2-nonenal (HNE) in nonpreconditioned rabbits. The accumulation of HNE was inhibited by late PC, and this effect was abrogated by sorbinil. Taken together, these results establish AR as an essential mediator of late PC. Furthermore, the data suggest that myocardial ischemia/reperfusion injury is due in part to the generation of lipid peroxidation products and that late PC diminishes this source of injury by upregulating AR.

Original languageEnglish (US)
Pages (from-to)240-246
Number of pages7
JournalCirculation research
Volume91
Issue number3
DOIs
StatePublished - Aug 9 2002

Keywords

  • 4-Hydroxy-trans-2-nonenal
  • Aldose reductase
  • Ischemic preconditioning
  • Myocardial infarction
  • Myocardial ischemia/reperfusion injury

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Shinmura, K., Bolli, R., Liu, S. Q., Tang, X. L., Kodani, E., Xuan, Y. T., Srivastava, S., & Bhatnagar, A. (2002). Aldose reductase is an obligatory mediator of the late phase of ischemic preconditioning. Circulation research, 91(3), 240-246. https://doi.org/10.1161/01.RES.0000029970.97247.57