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

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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.

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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

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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.

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  1. Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 333, Baltimore, MD, 21205, USA

    Zheqing P. Cai, Nirmal Parajuli, Xiaoxu Zheng & Lewis Becker

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Correspondence to Zheqing P. Cai.

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Cai, Z.P., Parajuli, N., Zheng, X. et al. Remote ischemic preconditioning confers late protection against myocardial ischemia–reperfusion injury in mice by upregulating interleukin-10. Basic Res Cardiol 107, 277 (2012). https://doi.org/10.1007/s00395-012-0277-1

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