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Endoplasmic reticulum stress contributes to heart protection induced by cyclophilin D inhibition

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Abstract

Preventing cyclophilin D (cypD) translocation to the inner mitochondrial membrane can limit lethal reperfusion injury through the inhibition of the opening of the mitochondrial permeability transition pore. Inhibition or loss of function of cypD may also result into an endoplasmic reticulum (ER) stress that has been shown to alter cell survival. We therefore questioned whether ER stress might play a role in the protection induced by CypD deficiency or inhibition. CypD-KO and NIM811 (a CypD inhibitor)-treated mice were subjected to a prolonged ischemia–reperfusion (I/R). Area at risk and infarct size was measured using blue dye and triphenyltetrazolium chloride staining. ER stress markers were measured in the hearts during the reperfusion phase. As expected, cypD-KO mice exhibited a decreased infarct size when compared to wild-type mice (8 ± 1 vs. 20 ± 4 % of left ventricular weight; p < 0.01). CypD-deficient mice displayed an increased expression of ER stress proteins such as eukaryotic initiation factor 2α (eIF2α) or glucose regulated protein 78 (Grp78 or Bip). The ER stress inhibitor TUDCA prevented the infarct size reduction afforded by the loss of cypD function (mean infarct size averaged 21 ± 4 % of LV weight, p < 0.01 vs. cypD-KO). Similar results were obtained when NIM811, an analog of cyclosporine A, was used to pharmacologically (instead of genetically) inhibit cypD function. This study suggests that the ER stress induced by the inhibition of cypD function plays a key role in protecting the heart against lethal ischemia–reperfusion injury.

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Acknowledgments

Elise Belaidi was the recipient of a Grant from La Fondation Lefoulon Delalande (France).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. CarMeN Laboratory, INSERM UMR-1060, Cardioprotection Team, Faculté de Médecine, Univ Lyon-1, 8 Avenue Rockefeller, 69373, Lyon Cedex 08, France

    Elise Belaidi, Johanna Decorps, Lionel Augeul, Annie Durand & Michel Ovize

  2. Service d’Explorations Fonctionnelles Cardiovasculaires and CIC de Lyon, Hôpital Louis Pradel, Hospices Civils de Lyon, 69677, Lyon, France

    Michel Ovize

  3. KP2 Laboratory, INSERM 1042, Faculté de Médecine-Pharmacie, Univ Grenoble-1, BP 170, Grenoble Cedex, France

    Elise Belaidi

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395_2013_363_MOESM1_ESM.pptx

Fig. S1 mRNA content of ER stress markers after inhibition of CypD by NIM811. RT-qPcR on eIF2S1a (a), Grp78 (b), CHOP (c) and spliced-Xbp (Xbps) (d) mRNA in ctrl, NIM and TUDCA + NIM groups. mRNA levels were normalized with murine β-glucuronidase (mGUSB). One-way ANOVA, student Newman–Keuls post hoc tests, ***p < 0.001 vs. ctrl group (PPTX 83 kb)

395_2013_363_MOESM2_ESM.pptx

Fig. S2 mRNA content of ER stress markers after TUDCA treatment alone. RT-qPcR on eIF2S1a (a), Grp78 (b), CHOP (c) and spliced-Xbp (Xbps) (d) mRNA in ctrl and TUDCA groups. mRNA levels were normalized with murine β-glucuronidase (mGUSB). One-way ANOVA, student Newman–Keuls post hoc tests, ***p < 0.001 vs. ctrl group (PPTX 71 kb)

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Belaidi, E., Decorps, J., Augeul, L. et al. Endoplasmic reticulum stress contributes to heart protection induced by cyclophilin D inhibition. Basic Res Cardiol 108, 363 (2013). https://doi.org/10.1007/s00395-013-0363-z

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