Dimethyloxalylglycine treatment of brain-dead donor rats improves both donor and graft left ventricular function after heart transplantation

Hegedűs, Péter; Li, Shiliang; Korkmaz‐Icöz, Sevil; Radovits, Tamás; Mayer, Tobias; Said, Samer Al; Brlecic, Paige; Kretzler, Matthias; Merkely, Béla; Szabó, Gábor

doi:10.1016/j.healun.2015.06.016

Cited by 20 publications

(23 citation statements)

References 38 publications

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“…Bernhardt and coworkers (12) have demonstrated that donor pretreated with a PHD inhibitor (FG-4497) could significantly improve graft function and survival in an allogeneic rodent model of renal transplantation via up-regulation of HIF-1a and its target genes. In a rat model of brain death (BD)-associated donor heart dysfunction, Heged} us et al (10) demonstrated that pretreatment with the PHD inhibitor DMOG resulted in improved early recovery of graft left ventricular function after heart transplantation, supported the hypothesis that activation of HIF-1a and its target genes has a protective role against BD-associated cardiac dysfunction. In addition, Amador et al (31) evaluated the clinical application of ischemic preconditioning (IPC) in deceased donor liver transplantation, the authors demonstrated improved hepatic enzyme levels and reduced reoperation rate in the IPC group with associated activation of the HIF-1 pathway.…”

Section: Discussionmentioning

confidence: 93%

“…Preconditional activation of HIF-1 by a HIF-agonist (EDHB) significantly decreases liver ischemia/reperfusion (I/R) injury through decreased mitochondrial depolarization and prevention of mitochondrial injury (8). The pharmaceutical activation of HIF-1 with the use of synthetic HIF agonists also results in early recovery of graft function in renal, heart and aortic allograft transplantation (9)(10)(11)(12)(13).…”

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confidence: 99%

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Donor Treatment With a Hypoxia‐Inducible Factor‐1 Agonist Prevents Donation After Cardiac Death Liver Graft Injury in a Rat Isolated Perfusion Model

et al. 2017

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The protective role of hypoxia-inducible factor-1 (HIF-1) against liver ischemia-reperfusion injury has been well proved. However its role in liver donation and preservation from donation after cardiac death (DCD) is still unknown. The objective of this study was to test the hypothesis that pharmaceutical stabilization of HIF-1 in DCD donors would result in a better graft liver condition. Male SD rats (6 animals per group) were randomly given the synthetic prolyl hydroxylase domain inhibitor FG-4592 (Selleck, 6 mg/kg of body weight) or its vehicle (dimethylsulfoxide). Six hours later, cardiac arrest was induced by bilateral pneumothorax. Rat livers were retrieved 30 min after cardiac arrest, and subsequently cold stored in University of Wisconsin solution for 24 h. They were reperfused for 60 min with Krebs-Henseleit bicarbonate buffer in an isolated perfused liver model, after which the perfusate and liver tissues were investigated. Pretreatment with FG-4592 in DCD donors significantly improved graft function with increased bile production and synthesis of adenosine triphosphate, decreased perfusate liver enzyme release, histology injury scores and oxidative stress-induced cell injury and apoptosis after reperfusion with the isolated perfused liver model. The beneficial effects of FG-4592 is attributed in part to the accumulation of HIF-1 and ultimately increased PDK1 production. Pretreatment with FG-4592 in DCD donors resulted in activation of the HIF-1 pathway and subsequently protected liver grafts from warm ischemia and cold-stored injury. These data suggest that the pharmacological HIF-1 induction may provide a clinically applicable therapeutic intervention to prevent injury to DCD allografts.

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Section: Discussionmentioning

confidence: 93%

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confidence: 99%

Donor Treatment With a Hypoxia‐Inducible Factor‐1 Agonist Prevents Donation After Cardiac Death Liver Graft Injury in a Rat Isolated Perfusion Model

et al. 2017

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“…Although most in vivo preclinical studies investigating the effects of PDE5 inhibitors were performed in experimental models of myocardial IR, a limited number of studies have been conducted in an in vivo model of global IR injury. In our laboratory, the effects of vardenafil on global IR injury were investigated using our well-established rat model of heterotopic heart transplantation (Szabo et al, 2002;Loganathan et al, 2015;Hegedus et al, 2016). Our results show that a preconditioning of donor rats with vardenafil (10 μg·kg À1 , i.v.…”

Section: Global Myocardial Ischaemia/reperfusion Injurymentioning

confidence: 88%

Targeting phosphodiesterase 5 as a therapeutic option against myocardial ischaemia/reperfusion injury and for treating heart failure

Korkmaz‐Icöz

Radovits

Szabó

2017

British J Pharmacology

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Phosphodiesterase type 5 (PDE5) selectively hydrolyses the second messenger cGMP into 5 0 -GMP, thereby regulating its intracellular concentrations. Dysregulation of the cGMP-dependent pathway plays a significant role in various cardiovascular diseases. Therefore, its modulation by drugs, such as PDE5 inhibitors, may represent an effective therapeutic approach. There are currently four PDE5 inhibitors available for the treatment of erectile dysfunction: sildenafil, vardenafil, tadalafil and avanafil. Sildenafil and tadalafil have also received Food and Drug Administration approval for the treatment of pulmonary arterial hypertension. This review summarizes the pharmacological aspects and clinical potential of PDE5 inhibition for the treatment of myocardial ischaemia/reperfusion injury and heart failure.This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc Abbreviations Bcl 2, B-cell lymphoma 2; HF, heart failure; IR, ischemia/reperfusion; KCa, calcium-activated potassium channel; LAD, left anterior descending artery; PGC-1α, PPAR gamma coactivator 1-alpha; SIRT1, sirtuin 1 LINKED ARTICLES

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“…The experimental model was described elsewhere (18)(19)(20). The experimental model was described elsewhere (18)(19)(20).…”

Section: Model Of Heterotopic Heart Transplantationmentioning

confidence: 99%

“…Based on published in vitro and in vivo findings, we hypothesized that the treatment of BDD with NOD improves both donor and graft left-ventricular (LV) function in our well-established rat model of heterotopic heart transplantation (18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Donor Preconditioning After the Onset of Brain Death With Dopamine Derivate n-Octanoyl Dopamine Improves Early Posttransplant Graft Function in the Rat

Korkmaz‐Icöz

Radovits

et al. 2017

American Journal of Transplantation

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Heart transplantation is the therapy of choice for end-stage heart failure. However, hemodynamic instability, which has been demonstrated in brain-dead donors (BDD), could also affect the posttransplant graft function. We tested the hypothesis that treatment of the BDD with the dopamine derivate n-octanoyl-dopamine (NOD) improves donor cardiac and graft function after transplantation. Donor rats were given a continuous intravenous infusion of either NOD (0.882 mg/kg/h, BDD+NOD, n = 6) or a physiological saline vehicle (BDD, n = 9) for 5 h after the induction of brain death by inflation of a subdural balloon catheter. Controls were sham-operated (n = 9). In BDD, decreased left-ventricular contractility (ejection fraction; maximum rate of rise of left-ventricular pressure; preload recruitable stroke work), relaxation (maximum rate of fall of left-ventricular pressure; Tau), and increased end-diastolic stiffness were significantly improved after the NOD treatment. Following the transplantation, the NOD-treatment of BDD improved impaired systolic function and ventricular relaxation. Additionally, after transplantation increased interleukin-6, tumor necrosis factor TNF-α, NF-kappaB-p65, and nuclear factor (NF)-kappaB-p105 gene expression, and increased caspase-3, TNF-α and NF-kappaB protein expression could be significantly downregulated by the NOD treatment compared to BDD. BDD postconditioning with NOD through downregulation of the pro-apoptotic factor caspase-3, pro-inflammatory cytokines, and NF-kappaB may protect the heart against the myocardial injuries associated with brain death and ischemia/reperfusion.

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Dimethyloxalylglycine treatment of brain-dead donor rats improves both donor and graft left ventricular function after heart transplantation

Cited by 20 publications

References 38 publications

Donor Treatment With a Hypoxia‐Inducible Factor‐1 Agonist Prevents Donation After Cardiac Death Liver Graft Injury in a Rat Isolated Perfusion Model

Donor Treatment With a Hypoxia‐Inducible Factor‐1 Agonist Prevents Donation After Cardiac Death Liver Graft Injury in a Rat Isolated Perfusion Model

Targeting phosphodiesterase 5 as a therapeutic option against myocardial ischaemia/reperfusion injury and for treating heart failure

Donor Preconditioning After the Onset of Brain Death With Dopamine Derivate n-Octanoyl Dopamine Improves Early Posttransplant Graft Function in the Rat

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