Open AccessROS ‐Mediated PARP Activity Undermines Mitochondrial Function After Permeability Transition Pore Opening During Myocardial Ischemia–Reperfusion
Author(s) -
Schriewer Jacqueline M.,
Peek Clara Bien,
Bass Joseph,
Schumacker Paul T.
Publication year - 2013
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.113.000159
Subject(s) - mitochondrial permeability transition pore , mptp , oxidative stress , poly adp ribose polymerase , mitochondrion , programmed cell death , reperfusion injury , medicine , ischemia , mitochondrial ros , nad+ kinase , pharmacology , apoptosis , microbiology and biotechnology , biology , biochemistry , polymerase , enzyme , dopaminergic , dopamine
Background Ischemia–reperfusion (I/R) studies have implicated oxidant stress, the mitochondrial permeability transition pore ( mPTP ), and poly(ADP‐ribose) polymerase ( PARP ) as contributing factors in myocardial cell death. However, the interdependence of these factors in the intact, blood‐perfused heart is not known. We therefore wanted to determine whether oxidant stress, mPTP opening, and PARP activity contribute to the same death pathway after myocardial I/R. Methods and Results A murine left anterior descending coronary artery ( LAD ) occlusion (30 minutes) and release (1 to 4 hours) model was employed. Experimental groups included controls and antioxidant‐treated, mPTP ‐inhibited, or PARP ‐inhibited hearts. Antioxidant treatment prevented oxidative damage, mPTP opening, ATP depletion, and PARP activity, placing oxidant stress as the proximal death trigger. Genetic deletion of cyclophilin D (CypD −/− ) prevented loss of total NAD + and PARP activity, and mPTP ‐mediated loss of mitochondrial function. Control hearts showed progressive mitochondrial depolarization and loss of ATP from 1.5 to 4 hours of reperfusion, but not outer mitochondrial membrane rupture. Neither genetic deletion of PARP ‐1 nor its pharmacological inhibition prevented the initial mPTP ‐mediated depolarization or loss of ATP , but PARP ablation did allow mitochondrial recovery by 4 hours of reperfusion. Conclusions These results indicate that oxidant stress, the mPTP , and PARP activity contribute to a single death pathway after I/R in the heart. PARP activation undermines cell survival by preventing mitochondrial recovery after mPTP opening early in reperfusion. This suggests that PARP ‐mediated prolongation of mitochondrial depolarization contributes significantly to cell death via an energetic crisis rather than by mitochondrial outer membrane rupture.