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Endoplasmic reticulum stress contributes to heart protection induced by cyclophilin D inhibition
Elise Belaidi1, Johanna Decorps, Lionel Augeul
1CarMeN Laboratory, INSERM UMR-1060, Cardioprotection Team, Faculté de Médecine, Univ Lyon-1, 8 Avenue Rockefeller, 69373, Lyon Cedex 08, France. elise.belaidi-corsat@ujf-grenoble.fr
Insights
Preventing cyclophilin D (cypD) translocation limits reperfusion injury. This study shows that endoplasmic reticulum (ER) stress, induced by cypD inhibition, plays a key role in this heart protection.
Area of Science:
- Cardiovascular Research
- Mitochondrial Biology
- Cellular Stress Response
Background:
- Cyclophilin D (cypD) translocation to the inner mitochondrial membrane contributes to lethal reperfusion injury by opening the mitochondrial permeability transition pore.
- Inhibition or loss of cypD function can induce endoplasmic reticulum (ER) stress, which influences cell survival.
- The role of ER stress in the protective mechanisms against ischemia-reperfusion (I/R) injury mediated by cypD deficiency or inhibition remains unclear.
Purpose of the Study:
- To investigate whether ER stress plays a role in the cardioprotection observed in models of cypD deficiency or inhibition.
- To elucidate the molecular mechanisms linking cypD inhibition, ER stress, and protection against I/R injury.
Main Methods:
- Mice with cypD deficiency (cypD-KO) and wild-type mice were subjected to prolonged ischemia-reperfusion (I/R).
- Infarct size was quantified using blue dye and triphenyltetrazolium chloride staining.
- ER stress markers (e.g., eIF2α, Grp78) were measured in cardiac tissue during reperfusion.
- Pharmacological inhibition of cypD using NIM811 and ER stress inhibition using TUDCA were employed.
Main Results:
- cypD-KO mice exhibited significantly reduced infarct size compared to wild-type controls (8 ± 1% vs. 20 ± 4% of left ventricular weight, p < 0.01).
- cypD-deficient hearts showed increased expression of ER stress proteins, including eukaryotic initiation factor 2α (eIF2α) and glucose-regulated protein 78 (Grp78/Bip).
- Treatment with the ER stress inhibitor TUDCA abolished the infarct size reduction in cypD-KO mice (mean infarct size 21 ± 4% of LV weight, p < 0.01 vs. cypD-KO).
- Pharmacological inhibition of cypD with NIM811 mimicked the protective effects of genetic deficiency, and this protection was also abrogated by TUDCA.
Conclusions:
- The inhibition of cypD function induces ER stress in the heart.
- ER stress, triggered by cypD inhibition, plays a critical role in conferring cardioprotection against lethal ischemia-reperfusion injury.
- Targeting cypD and modulating ER stress pathways represent potential therapeutic strategies for managing I/R injury.
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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