Targeting the NLRP3 inflammasome to reduce warm ischemic injury in donation after circulatory death heart

Quader, Mohammed; Mezzaroma, Eleonora; Kenning, Kristine; Toldo, Stefano

doi:10.1111/ctr.14044

Cited by 14 publications

(9 citation statements)

References 27 publications

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“…NLRP3 inflammasome is a major mediator of inflammation-mediated damage to the DCD heart. 4 We demonstrated in our lab that NLRP3 knockout mice were protected from ischemia/reperfusion injury associated with the DCD process. 4 In the present study, we show that inhibition of NLRP3 in DCD hearts improve the function and decreased the formation of active NLRP3 inflammasome (ie, decreased ASC protein levels in DCD NLRP3-I heart tissue).…”

Section: Discussionmentioning

confidence: 92%

“… 4 We demonstrated in our lab that NLRP3 knockout mice were protected from ischemia/reperfusion injury associated with the DCD process. 4 In the present study, we show that inhibition of NLRP3 in DCD hearts improve the function and decreased the formation of active NLRP3 inflammasome (ie, decreased ASC protein levels in DCD NLRP3-I heart tissue). NLRP3 inflammasome inhibitor has been shown to be cardioprotective following acute myocardial infarction in mice.…”

Section: Discussionmentioning

confidence: 92%

“…Upon implantation, reperfusion injury causes additional damage to the DCD heart.Myocardial ischemia/reperfusion injury activates the NACHT, LRR, and PYD domains-containing protein-3 (NLRP3) inflammasome, an established mediator of ischemic injury and pathological remodeling. 4,5 We studied the cardioprotective effects of NLRP3 inhibition in a DCD rat heterotopic HTx model.…”

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confidence: 99%

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Improving circulatory death donor heart function: A novel approach

et al. 2021

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Heart transplantation (HTx) is limited due to the availability of donor hearts. 1 Up to 20% of patients die awaiting HTx. 1 HTx numbers could increase by 56% if hearts donated after circulatory death (DCD) were used for transplantation. 2 Recent trials have shown that DCD heart transplantation is feasible. 3 However, innate to the DCD process is ischemia, ventricular wall stretching, and high catecholamine release. Upon implantation, reperfusion injury causes additional damage to the DCD heart.Myocardial ischemia/reperfusion injury activates the NACHT, LRR, and PYD domains-containing protein-3 (NLRP3) inflammasome, an established mediator of ischemic injury and pathological remodeling. 4,5 We studied the cardioprotective effects of NLRP3 inhibition in a DCD rat heterotopic HTx model. METHODSOur protocol (Figure 1) followed the Guide for the Care and Use of Laboratory Animals (National Institutes of Health Publication No. 86-23) and was approved by the Virginia Commonwealth University Institutional Animal Care and Utilization Committee.Sprague-Dawley rats (aged 8-10 weeks) were anesthetized (ketaminexylazine, 100-10 mg/kg), intubated, connected to a ventilator, and anticoagulated with heparin (1000 U/kg). A catheter was placed in the right carotid artery; vecuronium-bromide (1.2 mg/kg) was administered to paralyze the diaphragm. After 1 minute, the ventilator was disconnected to initiate DCD process. After 10 minutes, the heart was exposed, and the aorta was clamped distal to the brachiocephalic branch. Ice-cold University of Wisconsin (UW) solution (12 mL) was perfused through the carotid catheter to flush and cool the heart. To the treatment group of DCD hearts, NLRP3 inhibitor (NLRP3-I) 16773-34-0 (Sigma-Aldrich, St Louis, Mo) (50 mM) was added to the UW solution. Warm ischemia time (ie, time between ventilatory support withdrawal and UW solution infusion) for DCD hearts was 25 minutes. In the control beating-heart donor (CBD) group, ventilation was continued until cardiac arrest with UW solution without the ischemia period. Following infusion of UW solution, solution hearts were procured by dividing the pulmonary artery and aorta distally, then

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 92%

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confidence: 99%

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Improving circulatory death donor heart function: A novel approach

et al. 2021

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“…Furthermore, hydrogen gas inhalation can attenuate myocardial IRI in rats by the inhibition of oxidative stress and NLRP3-mediated pyroptosis ( Nie et al, 2021 ). Notably, Quader et al (2020) reported that the DCD procedure resulted in the activation of the NLRP3 inflammasome, which contributed to myocardial damage and dysfunction, while NLRP3 inflammasome inhibition ameliorated myocardial warm ischemia injury and improved DCD heart function. In line with the above findings, our study shows 25-min warm ischemia in the DCD hearts impairs the cardiac function of hearts during 105-min EVHP and leads to a significant increase in the level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-mediated pyroptosis.…”

Section: Discussionmentioning

confidence: 99%

Normothermic ex vivo Heart Perfusion Combined With Melatonin Enhances Myocardial Protection in Rat Donation After Circulatory Death Hearts via Inhibiting NLRP3 Inflammasome-Mediated Pyroptosis

Zeng

et al. 2021

Front. Cell Dev. Biol.

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ObjectiveThe adoption of hearts from donation after circulatory death (DCD) is a promising approach for the shortage of suitable organs in heart transplantation. However, DCD hearts suffer from serious ischemia/reperfusion injury (IRI). Recent studies demonstrate that nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-mediated pyroptosis is a novel target to ameliorate myocardial IRI. Melatonin is shown to inhibit NLRP3 inflammasome-mediated pyroptosis. Therefore, this study is designed to verify the hypothesis that melatonin can protect the heart graft preserved with ex vivo heart perfusion (EVHP) against myocardial IRI via inhibiting NLRP3 inflammasome-mediated pyroptosis in a rat model of DCD.MethodsDonor-heart rats were randomly divided into three groups: (1) Control group: non-DCD hearts were harvested from heart-beating rats and immediately preserved with allogenic blood-based perfusate at constant flow for 105 min in the normothermic EVHP system; (2) DCD-vehicle group; and (3) DCD-melatonin group: rats were subjected to the DCD procedure with 25 min of warm ischemia injury and preserved by the normothermic EVHP system for 105 min. Melatonin (200 μmol/L) or vehicle was perfused in the cardioplegia and throughout the whole EVHP period. Cardiac functional assessment was performed every 30 min during EVHP. The level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-mediated pyroptosis of heart grafts submitted to EVHP were evaluated.ResultsTwenty five-minute warm ischemia injury resulted in a significant decrease in the developed pressure (DP), dP/dtmax, and dP/dtmin of left ventricular of the DCD hearts, while the treatment with melatonin significantly increased the DP, dP/dtmax of the left ventricular of DCD hearts compared with DCD-vehicle group. Furthermore, warm ischemia injury led to a significant increase in the level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-mediated pyroptosis in the hearts preserved with EVHP. However, melatonin added in the cardioplegia and throughout the EVHP period significantly attenuated the level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-mediated pyroptosis compared with DCD-vehicle group.ConclusionEVHP combined with melatonin post-conditioning attenuates myocardial IRI in DCD hearts by inhibiting NLRP3 inflammasome-mediated pyroptosis, which might expand the donor pool by the adoption of transplantable DCD hearts.

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“…The beneficial effects of inflammasome inhibition in DCD hearts was previously confirmed in a mice NLR family pyrin domain containing 3 knockout model. 6 Although the current study focuses on left ventricle preservation, it would be of interest to determine the effect of inflammasome inhibition on the right side of the heart. There may be differences given the distinct embryonic origins of the left- and right-side chambers being derived from the primary and secondary heart fields, respectively.…”

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confidence: 99%