Endothelial Dysfunction After Long-term Cold Storage in HTK Organ Preservation Solutions: Effects of Iron Chelators and N-α-acetyl-l-histidine

Radovits, Tamás; Li, Lin; Zotkina, Julia; Koch, Achim; Rauen, Ursula; Köhler, Gernot; Kretzler, Matthias; Szabó, Gábor

doi:10.1016/j.healun.2007.11.002

Cited by 39 publications

(49 citation statements)

References 29 publications

(37 reference statements)

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“…This is reflected in the reduced ability for endothelium-dependent relaxation and decreased development of smooth muscle tone to a high potassium concentration (Garbe et al, 2011). Previous published data from our research group showed that short-term storage was not able to induce a marked deficit of functional integrity (Radovits et al, 2008). Therefore, an in vitro model of cold ischemic storage is not suited for reliable investigation of pharmacological attempts .…”

Section: Discussionmentioning

confidence: 98%

“…Because the major source of free radicals and oxidants produced during IR are activated leukocytes in vivo, which are absent in the present in vitro model, it was necessary to add an external oxidant source to the aortic rings to better simulate the clinical situation. Thus, the aortic rings were investigated in a similar manner, with additional exposure to hypochlorite (200 mM) for 30 minutes and rinsing before phenylephrine precontraction (Radovits et al, 2008). Special attention was paid during the preparation to avoid damaging the endothelium.…”

Section: Methodsmentioning

confidence: 99%

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Prolyl-Hydroxylase Inhibition Preserves Endothelial Cell Function in a Rat Model of Vascular Ischemia Reperfusion Injury

Barnucz

Veres

Hegedűs

et al. 2013

J Pharmacol Exp Ther

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Storage protocols of vascular grafts need further improvement against ischemia-reperfusion (IR) injury. Hypoxia elicits a variety of complex cellular responses by altering the activity of many signaling pathways, such as the oxygen-dependent prolylhyroxylase domain-containing enzyme (PHD). Reduction of PHD activity during hypoxia leads to stabilization and accumulation of hypoxia inducible factor (HIF) 1a. We examined the effects of PHD inhibiton by dimethyloxalylglycine on the vasomotor responses of isolated rat aorta and aortic vascular smooth muscle cells (VSMCs) in a model of cold ischemia/warm reperfusion. Aortic segments underwent 24 hours of cold ischemic preservation in saline or DMOG (dimethyloxalylglycine)-supplemented saline solution. We investigated endothelium-dependent and -independent vasorelaxations. To simulate IR injury, hypochlorite (NaOCl) was added during warm reperfusion. VSMCs were incubated in NaCl or DMOG solution at 4°C for 24 hours after the medium was changed for a supplied standard medium at 37°C for 6 hours. Apoptosis was assessed using the TUNEL method. Gene expression analysis was performed using quantitative real-time polymerase chain reaction. Cold ischemic preservation and NaOCl induced severe endothelial dysfunction, which was significantly improved by DMOG supplementation (maximal relaxation of aortic segments to acetylcholine: control 95% 6 1% versus NaOCl 44% 6 4% versus DMOG 68% 6 5%). Number of TUNEL-positive cell nuclei was significantly higher in the NaOCl group, and DMOG treatment significantly decreased apoptosis. Inducible heme-oxygenase 1 mRNA expressions were significantly higher in the DMOG group. Pharmacological modulation of oxygen sensing system by DMOG in an in vitro model of vascular IR effectively preserved endothelial function. Inhibition of PHDs could therefore be a new therapeutic avenue for protecting endothelium and vascular muscle cells against IR injury.

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Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Prolyl-Hydroxylase Inhibition Preserves Endothelial Cell Function in a Rat Model of Vascular Ischemia Reperfusion Injury

Barnucz

Veres

Hegedűs

et al. 2013

J Pharmacol Exp Ther

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“…Iron-mediated production of reactive oxygen species, impairment of Ca 21 homeostasis, and ATP depletion seem to be of instrumental importance in the sequel of hypothermic preservation injury (Rauen et al, 2000;Brinkkoetter et al, 2006;Bartels-Stringer et al, 2007;Radovits et al, 2008). Earlier reports have concluded that prolonged cold ischemic time is not a risk factor for decreased long-term survival in cardiac allograft recipients (Morgan et al, 2003), yet more recent studies have indicated that it is a predictor of a 5-year conditional mortality (Taylor et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Dopamine and Lipophilic Derivates Protect Cardiomyocytes against Cold Preservation Injury

Vettel

Hottenrott

et al. 2013

J Pharmacol Exp Ther

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Donor heart allografts are extremely susceptible to prolonged static cold storage. Because donor treatment with low-dose dopamine improves clinical outcome after heart transplantation, we tested the hypothesis that dopamine and its lipophilic derivate, N-octanoyl dopamine (NOD), protect cardiomyocytes from cold storage injury. Neonatal rat cardiomyocytes were treated with dopamine or NOD or left untreated and subsequently subjected to static cold storage (8-12 hours). Dopamine-and NOD-treated cardiomyocytes displayed a better viability compared with untreated cells after hypothermia. In untreated cardiomyocytes, cell damage was reflected by lactate dehydrogenase (LDH) release and a decrease in intracellular ATP. NOD was approximately 20-fold more potent than dopamine. Similarly to cardiomyocytes in vitro, rat hearts perfused with NOD before explantation showed significantly lower LDH release after static cold storage. ATP regeneration and spontaneous contractions after cold storage and rewarming only occurred in treated cardiomyocytes. Hypothermia severely attenuated isoprenaline-induced cAMP formation in control but not in dopamine-or NOD-treated cells. Esterified derivates of NOD with redox potential and lipophilic side chains reduced cell damage during cold storage similarly to NOD. In contrast to dopamine, neither NOD nor its derivates induced a significant b-adrenoceptor-mediated elevation of cellular cAMP levels. The b 1 -adrenoceptor antagonist atenolol and D 1 /D 2 receptor antagonist fluphenazine had no impact on the protective effect of NOD or dopamine. We conclude that dopamine as well as NOD treatment mitigates cold preservation injury to cardiomyocytes. The beneficial effects are independent of b-adrenoceptor or dopaminergic receptor stimulation but correlate with redox potential and lipophilic properties.

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“…Chelation of the iron by deferoxamine and lipophilic membrane-permeable LK-614 protects the myocardium and endothelium against iron-dependent hypothermic injury [87]. The authors have developed TiProtec, a new preservation solution, in which the role of antioxidants refers to iron chelators [88, 89].…”

Section: New Areas Of Focus In Opsmentioning

confidence: 99%

“…TiProtec is the modified Custodiol® (HTK) solution, which besides iron chelators (deferoxamine and LK-614) contains higher potassium concentration, amino acids (L-glycine and L-alanine) to inhibit hypoxic injury, arginine to increase NO supply, and N-acetyl-histidine instead of histidine as a buffer. It has been previously shown that replacing histidine with N-acetyl-histidine in Custodiol® improved endothelial function in isolated rat aorta [87]. In several experimental systems, TiProtec has demonstrated promising results in preservation of hepatocytes, vascular endothelium, and smooth muscle cells after cold storage and a period of warm reperfusion.…”

Section: New Areas Of Focus In Opsmentioning

confidence: 99%

Organ Preservation into the 2020s: The Era of Dynamic Intervention

Petrenko

Carnevale

Somov

et al. 2019

Transfus Med Hemother

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Organ preservation has been of major importance ever since transplantation developed into a global clinical activity. The relatively simple procedures were developed on a basic comprehension of low-temperature biology as related to organs outside the body. In the past decade, there has been a significant increase in knowledge of the sequelae of effects in preserved organs, and how dynamic intervention by perfusion can be used to mitigate injury and improve the quality of the donated organs. The present review focuses on (1) new information about the cell and molecular events impacting on ischemia/reperfusion injury during organ preservation, (2) strategies which use varied compositions and additives in organ preservation solutions to deal with these, (3) clear definitions of the developing protocols for dynamic organ perfusion preservation, (4) information on how the choice of perfusion solutions can impact on desired attributes of dynamic organ perfusion, and (5) summary and future horizons.

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Endothelial Dysfunction After Long-term Cold Storage in HTK Organ Preservation Solutions: Effects of Iron Chelators and N-α-acetyl-l-histidine

Cited by 39 publications

References 29 publications

Prolyl-Hydroxylase Inhibition Preserves Endothelial Cell Function in a Rat Model of Vascular Ischemia Reperfusion Injury

Prolyl-Hydroxylase Inhibition Preserves Endothelial Cell Function in a Rat Model of Vascular Ischemia Reperfusion Injury

Dopamine and Lipophilic Derivates Protect Cardiomyocytes against Cold Preservation Injury

Organ Preservation into the 2020s: The Era of Dynamic Intervention

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