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Identification of inducible nitric oxide synthase in peripheral blood cells as a mediator of myocardial ischemia/reperfusion injury

  • Yiru Guo
  • Santosh K. Sanganalmath
  • Wenjian Wu
  • Xiaoping Zhu
  • Yiming Huang
  • Wei Tan
  • Suzanne T. Ildstad
  • Qianhong Li
  • Roberto BolliEmail author
Original Contribution

Abstract

Although the late phase of ischemic preconditioning is known to be mediated by increased inducible nitric oxide synthase (iNOS) activity, controversy persists regarding the role of iNOS in ischemia/reperfusion (I/R) injury and, specifically, whether this protein is protective or detrimental. We hypothesized that iNOS is protective in myocytes but detrimental in inflammatory cells. To test this hypothesis, we created chimeric mice with iNOS-deficient peripheral blood cells by transplanting iNOS knockout (KO) bone marrow in wild-type (WT) mice after lethal irradiation. 2 months later, the mice underwent a 30-min coronary occlusion followed by 24 h of reperfusion. In WT naïve mice (iNOS+/+ naïve; group I, n = 17), infarct size was 56.9 ± 2.8% of the risk region. In iNOS KO naïve mice with whole-body iNOS deletion (iNOS−/− naïve; group II, n = 10), infarct size was comparable to group I (53.4 ± 3.5%). When irradiated WT mice received marrow from WT mice (iNOS+/+ chimera; group III, n = 10), infarct size was slightly reduced versus group I (44.3 ± 3.2%), indicating that irradiation and/or transplantation slightly decrease I/R injury. However, when WT mice received marrow from iNOS KO mice (iNOS−/− chimera; group IV, n = 14), infarct size was profoundly reduced (22.8 ± 2.1%, P < 0.05 vs. group III), indicating that selective deletion of iNOS from peripheral blood cells (with no change in myocardial iNOS content) induces protection against myocardial infarction. Together with our previous work showing the cardioprotective actions of NO donors, iNOS gene therapy, and cardiac-specific overexpression of iNOS, these data support a complex, dual role of iNOS in myocardial infarction (i.e., protective in myocytes but deleterious in blood cells). To our knowledge, this is the first study to identify a critical role of iNOS in peripheral blood cells as a mediator of myocardial I/R injury. The results support heretofore unknown differential actions of iNOS depending on cell source and have important translational implications.

Keywords

Inducible nitric oxide synthase Myocardial infarction Infarct size Chimeric mice 

Notes

Acknowledgments

This study was supported in part by NIH grants R01 HL55757, HL-70897, HL-76794, and P01HL78825.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Yiru Guo
    • 1
  • Santosh K. Sanganalmath
    • 1
  • Wenjian Wu
    • 1
  • Xiaoping Zhu
    • 1
  • Yiming Huang
    • 2
  • Wei Tan
    • 1
  • Suzanne T. Ildstad
    • 2
  • Qianhong Li
    • 1
  • Roberto Bolli
    • 1
    Email author
  1. 1.Institute of Molecular CardiologyUniversity of LouisvilleLouisvilleUSA
  2. 2.Institute for Cellular TherapeuticsUniversity of LouisvilleLouisvilleUSA

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