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Remote ischemic preconditioning confers late protection against myocardial ischemia–reperfusion injury in mice by upregulating interleukin-10

  • Zheqing P. CaiEmail author
  • Nirmal Parajuli
  • Xiaoxu Zheng
  • Lewis Becker
Original Contribution

Abstract

Remote ischemic preconditioning (RIPC) induces a prolonged late phase of multi-organ protection against ischemia–reperfusion (IR) injury. In the present study, we tested the hypothesis that RIPC confers late protection against myocardial IR injury by upregulating expression of interleukin (IL)-10. Mice were exposed to lower limb RIPC or sham ischemia. After 24 h, mice with RIPC demonstrated decreased myocardial infarct size and improved cardiac contractility following 30-min ischemia and 120-min reperfusion (I-30/R-120). These effects of RIPC were completely blocked by anti-IL-10 receptor antibodies. In IL-10 knockout mice, RIPC cardioprotection was lost, but it was mimicked by exogenous IL-10. Administration of IL-10 to isolated perfused hearts increased phosphorylation of the protein kinase Akt and limited infarct size after I-30/R-120. In wild-type mice, RIPC increased plasma and cardiac IL-10 protein levels and caused activation of Akt and endothelial nitric oxide synthase in the heart at 24 h, which was also blocked by anti-IL-10 receptor antibodies. In the gastrocnemius muscle, RIPC resulted in immediate inactivation of the phosphatase PTEN and activation of Stat3, with increased IL-10 expression 24 h later. Myocyte-specific PTEN inactivation led to increased Stat3 phosphorylation and IL-10 protein expression in the gastrocnemius muscle. Taken together, these results suggest that RIPC induces late protection against myocardial IR injury by increasing expression of IL-10 in the remote muscle, followed by release of IL-10 into the circulation, and activation of protective signaling pathways in the heart. This study provides a scientific basis for the use of RIPC to confer systemic protection against IR injury.

Keywords

Remote ischemic preconditioning Interleukin-10 Reperfusion injury Phosphatase and tensin homologue deleted on chromosome ten Stat3 

Abbreviations

eNOS

Endothelial nitric oxide synthase

IL-10R1

Interleukin 10 receptor subunit 1

IS

Infarct size

IR

Ischemia–reperfusion

LVDP

Left ventricular developed pressure

LY

LY294002

PI3K

Phosphatidylinositol-3-kinase

PTEN

Phosphatase and tensin homologue deleted on chromosome ten

PKO

Myocyte-specific PTEN knockout

RA

Anti-IL-10 receptor antibody

RIPC

Remote ischemic preconditioning

Stat3

Signal transducer and activator of transcription 3

STI

Stat3 inhibitor

Notes

Acknowledgments

This work was supported by Public Health Service grants HL88071 (to Z.P. Cai) and HL65608 (to L.C. Becker) from the National Heart, Lung and Blood Institute, National Institutes of Health.

Conflict of interest

None.

Supplementary material

395_2012_277_MOESM1_ESM.doc (32 kb)
Supplementary material 1 (DOC 32 kb)
395_2012_277_MOESM2_ESM.doc (34 kb)
Supplementary material 2 (DOC 34 kb)

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Zheqing P. Cai
    • 1
    Email author
  • Nirmal Parajuli
    • 1
  • Xiaoxu Zheng
    • 1
  • Lewis Becker
    • 1
  1. 1.Division of Cardiology, Department of MedicineJohns Hopkins University School of MedicineBaltimoreUSA

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