RIP3, a kinase promoting necroptotic cell death, mediates adverse remodelling after myocardial infarction

Luedde, Mark; Lutz, Matthias; Carter, Natalie; Sosna, Justyna; Jacoby, Christoph; Vucur, Mihael; Gautheron, Jérémie; Roderburg, Christoph; Borg, Nadine; Reisinger, Florian; Hippe, Hans-Joerg; Linkermann, Andreas; Wolf, Monika; Rose-John, Stefan; Lüllmann‐Rauch, Renate; Adam, Dieter; Flögel, Ulrich; Heikenwälder, Mathias; Luedde, Tom; Frey, Norbert

doi:10.1093/cvr/cvu146

Cited by 258 publications

(269 citation statements)

References 35 publications

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“…4C). Meanwhile, when compared to I/R alone, the addition of Z‐VAD alone in I/R rats did not affect the expression of RIP3, which is the key kinase in promoting necroptotic cell death 36. Accordingly, it could be speculated that the necroptotic epithelial cell death is likely to account for the mucosal injury after caspase inhibition.…”

Section: Discussionmentioning

confidence: 98%

Necroptosis is a key mediator of enterocytes loss in intestinal ischaemia/reperfusion injury

Wen

Ling

Yang

et al. 2016

J Cellular Molecular Medi

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Cell death is an important biological process that is believed to have a central role in intestinal ischaemia/reperfusion (I/R) injury. While the apoptosis inhibition is pivotal in preventing intestinal I/R, how necrotic cell death is regulated remains unknown. Necroptosis represents a newly discovered form of programmed cell death that combines the features of both apoptosis and necrosis, and it has been implicated in the development of a range of inflammatory diseases. Here, we show that receptor‐interacting protein 1/3 (RIP1/3) kinase and mixed lineage kinase domain‐like protein recruitment mediates necroptosis in a rat model of ischaemic intestinal injury in vivo. Furthermore, necroptosis was specifically blocked by the RIP1 kinase inhibitor necrostatin‐1. In addition, the combined treatment of necrostatin‐1 and the pan‐caspase inhibitor Z‐VAD acted synergistically to protect against intestinal I/R injury, and these two pathways can be converted to one another when one is inhibited. In vitro, necrostatin‐1 pre‐treatment reduced the necroptotic death of oxygen‐glucose deprivation challenged intestinal epithelial cell‐6 cells, which in turn dampened the production of pro‐inflammatory cytokines (tumour necrosis factor‐α and interleukin‐1β), and suppressed high‐mobility group box‐1 (HMGB1) translocation from the nucleus to the cytoplasm and the subsequent release of HMGB1 into the supernatant, thus decreasing the activation of Toll‐like receptor 4 and the receptor for advanced glycation end products. Collectively, our study reveals a robust RIP1/RIP3‐dependent necroptosis pathway in intestinal I/R‐induced intestinal injury in vivo and in vitro and suggests that the HMGB1 signalling is highly involved in this process, making it a novel therapeutic target for acute ischaemic intestinal injury.

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Section: Discussionmentioning

confidence: 98%

Necroptosis is a key mediator of enterocytes loss in intestinal ischaemia/reperfusion injury

Wen

Ling

Yang

et al. 2016

J Cellular Molecular Medi

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“…In a study using an in vivo model of myocardial infarction 24 hours after permanent ligation of the left anterior descending coronary artery, overexpression of RIPК3 was detected via an immunoblot test in mouse hearts (10). In that study, RIPК3-deficient mice had a significantly better ejection fraction and less hypertrophy in magnetic resonance imaging (MRI) studies 30 days after experimental infarction in comparison to wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

“…Similar to apoptosis, this process is tightly regulated by distinct molecules and has morphological features of both necrosis and inflammation (3,(6)(7)(8)(9). Nevertheless, the exact pathways activating this programmed necrosis are not fully understood (10). A study has shown that tumor necrosis factor alpha (TNF-α) is a factor that triggers the formation of a complex, called necrosome, in the cytoplasm between receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3) (7).…”

Section: Introductionmentioning

confidence: 99%

Serum levels of RIPK3 and troponin I as potential biomarkers for predicting impaired left ventricular function in patients with myocardial infarction with ST segment elevation and normal troponin I levels prior percutaneous coronary intervention

Kashlov

Donev

Doneva

et al. 2016

BST

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“…RIP3 co‐localized with mitochondria when necrosis was induced in a kinase activity‐dependent manner and promoted mitochondrial metabolism and ROS production by activating the PYGL, GLUL and GLUD1, leading to the consequent necrosis as mentioned above (Figures 3 and 4). 60 In a recent study, Ting Zhang et al found that siRNA‐mediated knockdown of Cypd markedly alleviated RIP3‐induced cardiomyocyte necrosis as assessed by cellular ATP content and LDH release, further revealing the close relationship between these 2 pathways 61…”

Section: Signalling Interactionmentioning

confidence: 98%

“…As necrosis can be induced by the activation of the death receptors, it is not surprised that RIP1/RIP3‐mediated death receptor pathway contributes to the necrosis of cardiomyocytes in heart failure patients. In the permanent myocardial ischaemia animal model, RIP3 knockout would decrease the inflammatory response and hypertrophic growth of the cells while the ejection fraction was increased 60. It had been also observed that the markers of necrosis, phospho‐MLKL, are also up regulated in the end‐stage heart failure patients 71.…”

Section: Necrosis In Heart Diseasesmentioning

confidence: 99%

Molecular mechanism and therapy application of necrosis during myocardial injury

Ding

Tariq

et al. 2018

J Cellular Molecular Medi

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Necrosis is an ancient topic which gains new attraction in the research area these years. There is no doubt that some necrosis can be regulated by genetic manipulation other than an accidental cell death resulting from physical or chemical stimuli. Recent advances in the molecular mechanism underlying the programmed necrosis show a fine regulation network which indicates new therapy targets in human diseases. Heart diseases seriously endanger our health and have high fatality rates in the patients. Cell death of cardiac myocytes is believed to be critical in the pathogenesis of heart diseases. Although necrosis is likely to play a more important role in cardiac cell death than apoptosis, apoptosis has been paid much attention in the past 30 years because it used to be considered as the only form of programmed cell death. However, recent findings of programmed necrosis and the related signalling pathways have broadened our horizon in the field of programmed cell death and promote new pharmacological application in the treatment of heart diseases. In this review, we summarize the advanced progress in these signalling pathways and discuss the pathos‐physiological relevance and therapeutic implication of targeting necrosis in heart diseases treatment.

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RIP3, a kinase promoting necroptotic cell death, mediates adverse remodelling after myocardial infarction

Abstract: Here, we show that RIP3-dependent necroptosis modulates post-ischaemic adverse remodelling in a mouse model of MI. This novel signalling pathway may thus be an attractive target for future therapies that aim to limit the adverse consequences of myocardial ischaemia.

Cited by 258 publications

References 35 publications

Necroptosis is a key mediator of enterocytes loss in intestinal ischaemia/reperfusion injury

Necroptosis is a key mediator of enterocytes loss in intestinal ischaemia/reperfusion injury

Serum levels of RIPK3 and troponin I as potential biomarkers for predicting impaired left ventricular function in patients with myocardial infarction with ST segment elevation and normal troponin I levels prior percutaneous coronary intervention

Molecular mechanism and therapy application of necrosis during myocardial injury

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