INCREASED CARDIAC MITOCHONDRIAL-DERIVED VESICLE FORMATION IN RESPONSE TO ACUTE STRESS AND DOXORUBICIN-INDUCED CARDIOTOXICITY

Abstract

s S65 METHODS/RESULTS: Using cultured H9c2 cardioblasts, treatment with common mitochondrial stressors (antimycin-A and H2O2) resulted in a significant increase in MDV formation after only 60 min of exposure. The chemotherapeutic agent doxorubicin (DOXO) induced time-dependent MDV production with maximal formation occurring after 30 min of treatment, followed by a gradual, time-dependent decrease in MDV levels towards baseline (achieved at 24h). In vivo MDV formation and response to stress was studied in mice subjected to either Sham injections or acute DOXO treatment (2x15mg/kg, 48 hours apart) followed by 5 days recovery. Despite the absence of gross echocardiographic differences between groups, mitochondrial functional analysis revealed decreased mitochondrial respiratory capacity, increased ROS production, and susceptibility to permeability transition pore opening in the DOXO treated group. Morphological analysis and identification of MDVs by TEM was validated by electron tomography and immunogold labelling and revealed a substantial increase in the number of MDVs in the heart of DOXO-treated animals. CONCLUSION: Our results thus demonstrate that in a cardiac cell model MDV formation is a fast-response mechanism of mitochondrial QC stimulated bymitochondrial and cellular stressors. Moreover, in addition to the previous reports of in vitro MDV formation, this study demonstrates the existence and responsiveness of MDV formation in cardiac mitochondrial QC. Fonds de recherche du Quebec e Sante 130 FATTY ACID OXIDATION INHIBITION AS A POTENTIAL NOVEL TREATMENT STRATEGY IN PULMONARY ARTERY HYPERTENSION AND RIGHT HEART FAILURE A Ahmadi, JM Renaud, J Petryk, T Hadizad, TD Ruddy, JR Dyck, RS Beanlands, RA deKemp, GD Lopaschuk, LM Mielniczuk