Modulation of Mitochondrial Respiration During Early Reperfusion Reduces Cardiac Injury in Donation After Circulatory Death Hearts

Akande, Oluwatoyin; Chen, Qun; Cholyway, Renee; Toldo, Stefano; Lesnefsky, Edward J.; Quader, Mohammed

doi:10.1097/fjc.0000000000001290

Cited by 6 publications

(3 citation statements)

References 45 publications

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“…Mitochondria ETC plays a vital role in oxidative stress under either physiological or pathological conditions [32]. Since numerous experiments have demonstrated that blocking the ETC can reduce the oxidative stress injury of myocardial cells [18], such as amobarbital [16,33]. In our study, fow cytometry analysis suggested that the reduction of Ndufs4 subunit expression can decrease the H9c2 apoptosis ratio from 40% to 18%, and mitigate H9c2 injury.…”

Section: Discussionmentioning

confidence: 51%

Recombinant Adenovirus siRNA Knocking Down the Ndufs4 Gene Alleviates Myocardial Apoptosis Induced by Oxidative Stress Injury

Wang

Zhang

2023

Cardiology Research and Practice

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Oxidative stress results in myocardial cell apoptosis and even life-threatening heart failure in myocardial ischemia-reperfusion injury. Specific blocking of the complex I could reduce cell apoptosis. Ndufs4 is a nuclear-encoded subunit of the mitochondrial complex I and participates in the electron transport chain. In this study, we designed and synthesized siRNA sequences knocking down the rat Ndufs4 gene, constructed recombinant adenovirus Ndufs4 siRNA (Ad-Ndufs4 siRNA), and primarily verified the role of Ndufs4 in oxidative stress injury. The results showed that the adenovirus infection rate was about 90%, and Ndufs4 mRNA and protein were decreased by 76.7% and 64.9%, respectively. Furthermore, the flow cytometry assay indicated that the cell apoptosis rate of the Ndufs4 siRNA group was significantly decreased as compared with the H2O2-treated group. In conclusion, we successfully constructed Ndufs4 siRNA recombinant adenovirus; furthermore, the downexpression of the Ndufs4 gene may alleviate H2O2-induced H9c2 cell apoptosis.

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Section: Discussionmentioning

confidence: 51%

Recombinant Adenovirus siRNA Knocking Down the Ndufs4 Gene Alleviates Myocardial Apoptosis Induced by Oxidative Stress Injury

Wang

Zhang

2023

Cardiology Research and Practice

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“…Inhibition of this process with malonate is cardioprotective and would also be expected to improve cardiac recovery following DCD [112]. Indeed, in a rat model of DCD, the transient inhibition of mitochondrial complex I during early reperfusion led to reduced cardiac injury, likely due to decreased ROS production [113]. Also, an inhibitor of reverse electron transport (RET), which is a key mechanism for mitochondrial ROS production during reperfusion, could be used [111], or indeed, ROS scavengers.…”

Section: Potential Metabolic-based Cardioprotective (Reperfusion) Str...mentioning

confidence: 99%

Metabolic Considerations in Direct Procurement and Perfusion Protocols with DCD Heart Transplantation

Arnold,

Do,

Davidson

et al. 2024

IJMS

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Heart transplantation with donation after circulatory death (DCD) provides excellent patient outcomes and increases donor heart availability. However, unlike conventional grafts obtained through donation after brain death, DCD cardiac grafts are not only exposed to warm, unprotected ischemia, but also to a potentially damaging pre-ischemic phase after withdrawal of life-sustaining therapy (WLST). In this review, we aim to bring together knowledge about changes in cardiac energy metabolism and its regulation that occur in DCD donors during WLST, circulatory arrest, and following the onset of warm ischemia. Acute metabolic, hemodynamic, and biochemical changes in the DCD donor expose hearts to high circulating catecholamines, hypoxia, and warm ischemia, all of which can negatively impact the heart. Further metabolic changes and cellular damage occur with reperfusion. The altered energy substrate availability prior to organ procurement likely plays an important role in graft quality and post-ischemic cardiac recovery. These aspects should, therefore, be considered in clinical protocols, as well as in pre-clinical DCD models. Notably, interventions prior to graft procurement are limited for ethical reasons in DCD donors; thus, it is important to understand these mechanisms to optimize conditions during initial reperfusion in concert with graft evaluation and re-evaluation for the purpose of tailoring and adjusting therapies and ensuring optimal graft quality for transplantation.

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“…6 In an ex vivo ischemia-reperfusion model, when AMO was administered during early reperfusion, it decreased cardiac injury in DCD hearts. 7 The beneficial effects of AMO in in vivo ischemia-reperfusion settings were not studied; hence, we elected to study the contribution of AMO treatment during reperfusion to improve function in transplanted DCD hearts when added to a standard cardioplegic solution.…”

Section: Introductionmentioning

confidence: 99%

Electron Transport Chain Inhibition to Decrease Reperfusion Injury in Transplanted Donation after Circulatory Death Rat Hearts

Quader

Chen

Akande

et al. 2023

Journal of Cardiovascular Pharmacology

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Donation after circulatory death (DCD) donor hearts sustain ischemic damage and are not routinely used for heart transplantation. DCD heart injury, particularly reperfusion injury, is primarily mediated by releasing reactive oxygen species from the damaged mitochondria (complex I of the electron transport chain). Amobarbital (AMO) is a transient inhibitor of complex I and is known to reduce releasing reactive oxygen species generation. We studied the beneficial effects of AMO in transplanted DCD hearts. Sprague-Dawley rats were assigned to 4 groups-DCD or DCD + AMO donors and control beating-heart donors (CBD) or CBD + AMO donors (n = 6-8 each). Anesthetized rats were connected to a ventilator. The right carotid artery was cannulated, heparin and vecuronium were administered. The DCD process started by disconnecting the ventilator. DCD hearts were procured after 25 minutes of in-vivoischemia, whereas CBD hearts were procured without ischemia. At procurement, all donor hearts received 10 mL of University of Wisconsin cardioplegia solution. The CBD + AMO and DCD + AMO groups received AMO (2 mM) dissolved in cardioplegia. Heterotopic heart transplantation was performed by anastomosing the donor aorta and pulmonary artery to the recipient's abdominal aorta and inferior vena cava. After 14 days, transplanted heart function was measured with a balloon tip catheter placed in the left ventricle. Compared with CBD hearts, DCD hearts had significantly lower developed pressure. AMO treatment significantly improved cardiac function in DCD hearts. Treatment of DCD hearts at the time of reperfusion with AMO resulted in an improvement of transplanted heart function that was comparable with the CBD hearts.

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Modulation of Mitochondrial Respiration During Early Reperfusion Reduces Cardiac Injury in Donation After Circulatory Death Hearts

Cited by 6 publications

References 45 publications

Recombinant Adenovirus siRNA Knocking Down the Ndufs4 Gene Alleviates Myocardial Apoptosis Induced by Oxidative Stress Injury

Recombinant Adenovirus siRNA Knocking Down the Ndufs4 Gene Alleviates Myocardial Apoptosis Induced by Oxidative Stress Injury

Metabolic Considerations in Direct Procurement and Perfusion Protocols with DCD Heart Transplantation

Electron Transport Chain Inhibition to Decrease Reperfusion Injury in Transplanted Donation after Circulatory Death Rat Hearts

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