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Updated: May 12, 2026
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
ROS-mediated PARP activity undermines mitochondrial function after permeability transition pore opening during
Jacqueline M Schriewer1, Clara Bien Peek, Joseph Bass
1Division of Neonatology, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
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.
Insights
Oxidant stress triggers myocardial cell death after ischemia-reperfusion (I/R). Poly(ADP-ribose) polymerase (PARP) activation prevents mitochondrial recovery, prolonging depolarization and causing an energetic crisis.
Area of Science:
- Cardiovascular Research
- Cellular and Molecular Biology
- Pathophysiology
Background:
- Ischemia-reperfusion (I/R) injury involves oxidant stress, mitochondrial permeability transition pore (mPTP) opening, and poly(ADP-ribose) polymerase (PARP) activation in myocardial cell death.
- The interdependence of these factors in the intact heart remains unclear.
Purpose of the Study:
- To determine if oxidant stress, mPTP opening, and PARP activity contribute to a unified death pathway following myocardial I/R.
- Investigate the sequential roles of these factors in cardiac I/R injury.
Main Methods:
- Utilized a murine model of left anterior descending coronary artery occlusion and release.
- Employed antioxidant treatment, mPTP inhibition, and PARP inhibition/ablation.
- Assessed oxidative damage, mPTP opening, ATP levels, NAD+ levels, and mitochondrial function.
Main Results:
- Antioxidant treatment identified oxidant stress as the primary trigger, preventing subsequent mPTP opening, ATP depletion, and PARP activity.
- Genetic deletion of cyclophilin D (CypD) inhibited PARP activity and preserved mitochondrial function.
- PARP inhibition/ablation did not prevent initial mPTP opening or ATP loss but facilitated mitochondrial recovery.
- Hearts exhibited mitochondrial depolarization and ATP depletion without outer membrane rupture during reperfusion.
Conclusions:
- Oxidant stress, mPTP opening, and PARP activity converge on a single myocardial cell death pathway during I/R.
- PARP activation hinders cell survival by impeding mitochondrial recovery post-mPTP opening.
- Prolonged mitochondrial depolarization due to PARP activity leads to cell death via energetic crisis, not outer membrane rupture.
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