Inhibition of myocardial reperfusion injury by ischemic postconditioning requires sirtuin 3-mediated deacetylation of cyclophilin D

Autor: Michel Ovize, Delphine Baetz, L. Ferreras, M. Strina, C. Crola-Da-Silva, Camille Villedieu, Abdallah Gharib, Bruno Pillot, Muhammad Rizwan Alam, Hélène Thibault, Thomas Bochaton
Přispěvatelé: Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA)
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Male
Survival
[SDV]Life Sciences [q-bio]
030204 cardiovascular system & hematology
Pharmacology
Mitochondrion
Mitochondrial Membrane Transport Proteins
Cyclophilins
Mice
0302 clinical medicine
Sirtuin 3
Myocyte
Cyclophilins/*metabolism
Ischemic Postconditioning
Membrane Potential
Mitochondrial
Mice
Knockout
0303 health sciences
biology
Cell Death
Ischemia-reperfusion
Acetylation
Cell Hypoxia
Biochemistry
Sirtuin
Cardiology and Cardiovascular Medicine
Cyclophilin D
Programmed cell death
SIRT3
Knockout
Post-conditioning
Myocardial Reperfusion Injury
Membrane Potential
03 medical and health sciences
Myocardial Reperfusion Injury/*metabolism
medicine
Animals
Molecular Biology
030304 developmental biology
Oxygen/pharmacology
Mitochondrial Permeability Transition Pore
Mitochondrial/drug effects
medicine.disease
Rats
Oxygen
Sirtuin 3/*metabolism
Mitochondrial permeability transition pore
biology.protein
Reperfusion injury
Zdroj: Journal of Molecular and Cellular Cardiology
Journal of Molecular and Cellular Cardiology, Elsevier, 2015, 84, pp.61-9. ⟨10.1016/j.yjmcc.2015.03.017⟩
Journal of Molecular and Cellular Cardiology, Elsevier, 2015, 84, pp.61-69. ⟨10.1016/j.yjmcc.2015.03.017⟩
ISSN: 0022-2828
1095-8584
Popis: International audience; RATIONALE: How ischemic postconditioning can inhibit opening of the mitochondrial permeability transition pore (PTP) and subsequent cardiac myocytes death at reperfusion remains unknown. Recent studies have suggested that de-acetylation of cyclophilin D (CyPD) by sirtuin 3 (SIRT3) can modulate its binding to the PTP. OBJECTIVE: The aim of the present study was to examine whether ischemic postconditioning (PostC) might activate SIRT3 and consequently prevent lethal myocardial reperfusion injury through a deacetylation of CyPD. METHODS AND RESULTS: Using hypoxia-reoxygenation (H/R) in H9C2 cells, we showed that SIRT3 overexpression prevented CyPD acetylation, limited PTP opening and reduced cell death by 24%. In vitro modification of the CyPD acetylation status in MEFs by site-directed mutagenesis altered capacity of PTP opening by calcium. Calcium Retention Capacity (CRC) was significantly decreased with CyPD-KQ that mimics acetylated protein compared with CyPD WT (871 +/- 266 vs 1193 +/- 263 nmoles Ca(2+)/mg protein respectively). Cells expressing non-acetylable CyPD mutant (CyPD-KR) displayed 20% decrease in cell death compared to cells expressing CyPD WT after H/R. Correspondingly, in mice we showed that cardiac ischemic postconditioning could not reduce infarct size and CyPD acetylation in SIRT3 KO mice, and was unable to restore CRC in mitochondria as it is observed in WT mice. CONCLUSIONS: Our study suggests that the increased acetylation of CyPD following myocardial ischemia-reperfusion facilitates PTP opening and subsequent cell death. Therefore ischemic postconditioning might prevent lethal reperfusion injury through an increased SIRT3 activity and subsequent attenuation of CyPD acetylation at reperfusion.
Databáze: OpenAIRE
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