Increase in Cardiac Ischemia-Reperfusion Injuries in Opa1+/- Mouse Model

Sophie Le Page (1) , Marjorie Niro (1) , J. Fauconnier (2) , Laura Cellier (1) , Sophie Tamareille (1) , Abdallah Gharib (3) , Arnaud Chevrollier (1) , Laurent Loufrani (1) , Céline Grenier (1) , Rima Kamel (1) , Emmanuelle Sarzi (4) , Alain Lacampagne (2) , Michel Ovize (3) , Daniel Henrion (5) , Pascal Reynier (1) , Guy Lenaers (1) , Delphine Mirebeau-Prunier (1) , Fabrice Prunier (6)

1 CHU Angers - Centre Hospitalier Universitaire d'Angers
2 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
3 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
4 INM - Institut des Neurosciences de Montpellier
5 BNMI - Biologie Neurovasculaire et Mitochondriale Intégrée
6 CRT - Cardioprotection, Remodelage et Thrombose

Background: Recent data suggests the involvement of mitochondrial dynamics in cardiac ischemia/reperfusion (I/R) injuries. Whilst excessive mitochondrial fission has been described as detrimental, the role of fusion proteins in this context remains uncertain. Objectives: To investigate whether Opa1 (protein involved in mitochondrial inner-membrane fusion) deficiency affects I/R injuries. Methods and Results: We examined mice exhibiting Opa1delTTAG mutations (Opa1+/-), showing 70% Opa1 protein expression in the myocardium as compared to their wild-type (WT) littermates. Cardiac left-ventricular systolic function assessed by means of echocardiography was observed to be similar in 3-month-old WT and Opa1+/- mice. After subjection to I/R, infarct size was significantly greater in Opa1+/- than in WTs both in vivo (43.2±4.1% vs. 28.4±3.5%, respectively; p<0.01) and ex vivo (71.1±3.2% vs. 59.6±8.5%, respectively; p<0.05). No difference was observed in the expression of other main fission/fusion protein, oxidative phosphorylation, apoptotic markers, or mitochondrial permeability transition pore (mPTP) function. Analysis of calcium transients in isolated ventricular cardiomyocytes demonstrated a lower sarcoplasmic reticulum Ca2+ uptake, whereas cytosolic Ca2+ removal from the Na+/Ca2+ exchanger (NCX) was increased, whilst SERCA2a, phospholamban, and NCX protein expression levels were unaffected in Opa1+/- compared to WT mice. Simultaneous whole-cell patch-clamp recordings of mitochondrial Ca2+ movements and ventricular action potential (AP) showed impairment of dynamic mitochondrial Ca2+ uptake and a marked increase in the AP late repolarization phase in conjunction with greater occurrence of arrhythmia in Opa1+/- mice. Conclusion: Opa1 deficiency was associated with increased sensitivity to I/R, imbalance in dynamic mitochondrial Ca2+ uptake, and subsequent increase in NCX activity.

Domaines: Cardiologie et système cardiovasculaire

Sophie Le Page, Marjorie Niro, J. Fauconnier, Laura Cellier, Sophie Tamareille, et al.. Increase in Cardiac Ischemia-Reperfusion Injuries in Opa1+/- Mouse Model. PLoS ONE, 2016, 11 (10), pp.e0164066. ⟨10.1371/journal.pone.0164066⟩. ⟨hal-01818418⟩