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HDL protects against ischemia reperfusion injury by preserving mitochondrial integrity

  • Miguel A. Frias
    Correspondence
    Corresponding author. Lipoprotein Research Group, Division of Endocrinology, Diabetology, Hypertension and Nutrition, University Hospital, 4, rue Gabrielle-Perret-Gentil, CH-1211 Geneva 14, Switzerland. Tel.: +41 22 3729303; fax: +41 22 3729329.
    Affiliations
    Division of Endocrinology, Diabetology, Hypertension and Nutrition, University Hospital Geneva, Switzerland

    Hatter Institute for Cardiovascular Research in Africa and MRC inter-University Cape Heart Group, Faculty of Health Science, University of Cape Town, South Africa
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  • Sarah Pedretti
    Affiliations
    Hatter Institute for Cardiovascular Research in Africa and MRC inter-University Cape Heart Group, Faculty of Health Science, University of Cape Town, South Africa
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  • Damian Hacking
    Affiliations
    Hatter Institute for Cardiovascular Research in Africa and MRC inter-University Cape Heart Group, Faculty of Health Science, University of Cape Town, South Africa
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  • Sarin Somers
    Affiliations
    Hatter Institute for Cardiovascular Research in Africa and MRC inter-University Cape Heart Group, Faculty of Health Science, University of Cape Town, South Africa
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  • Lydia Lacerda
    Affiliations
    Hatter Institute for Cardiovascular Research in Africa and MRC inter-University Cape Heart Group, Faculty of Health Science, University of Cape Town, South Africa
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  • Lionel H. Opie
    Affiliations
    Hatter Institute for Cardiovascular Research in Africa and MRC inter-University Cape Heart Group, Faculty of Health Science, University of Cape Town, South Africa
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  • Richard W. James
    Affiliations
    Division of Endocrinology, Diabetology, Hypertension and Nutrition, University Hospital Geneva, Switzerland
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  • Sandrine Lecour
    Affiliations
    Hatter Institute for Cardiovascular Research in Africa and MRC inter-University Cape Heart Group, Faculty of Health Science, University of Cape Town, South Africa
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      Abstract

      Objective

      High density lipoproteins (HDL) protect against ischemia reperfusion injury (IRI). However the precise mechanisms are not clearly understood. The novel intrinsic prosurvival signaling pathway named survivor activating factor enhancement (SAFE) path involves the activation of tumor necrosis factor (TNF) alpha and signal transducer and activator of transcription 3 (STAT3). SAFE plays a crucial role in cardioprotection against IRI. We propose that HDL protect against IRI via activation of the SAFE pathway and modulation of the mitochondrial permeability transition pore (mPTP) opening.

      Methods and results

      Isolated mouse hearts were subjected to global ischemia (35 min) followed by reperfusion (45 min). HDL were given during the first 7 min of reperfusion. In control hearts, the post-reperfusion infarct size was 41.3 ± 2.3%. Addition of HDL during reperfusion reduced the infarct size in a dose-dependent manner (HDL 200 μg protein/ml: 25.5 ± 1.6%, p < 0.001 vs. control). This protective effect was absent in TNF deficient mice (TNF-KO) or cardiomyocyte-STAT3 deficient mice (STAT3-KO). Similarly, HDL, given as a preconditioning stimulus, improved cell survival and inhibited mPTP opening in isolated cardiomyocytes subjected to simulated ischemia. These protective responses were inhibited in cardiomyocytes from TNF-KO and STAT3-KO mice.

      Conclusion

      Our data demonstrate that HDL protect against IRI by inhibition of mPTP opening, an effect mediated via activation of the SAFE pathway.

      Highlights

      • HDL protect against lethal ischemia reperfusion injury.
      • HDL induce cardioprotection by preserving mitochondrial integrity.
      • TNFα and STAT3 are required for HDL-induced cardioprotection.

      Keywords

      Abbreviations:

      IRI (ischemia reperfusion injury), HDL (high density lipoproteins), TNF (tumor necrosis factor alpha), STAT3 (signal transducer and activator of transcription 3), VDAC (voltage-dependent anion selective channel), mPTP (mitochondrial permeability transition pore), SAFE (survivor activating factor enhancement)
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