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Article

Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling

1
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, 81499 Bratislava, Slovakia
2
Faculty of Health Sciences, Bristol Heart Institute, The Bristol Medical School, University of Bristol, Bristol BS8 1TH, UK
3
Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 81438 Bratislava, Slovakia
*
Author to whom correspondence should be addressed.
Academic Editor: Robert Garfield
Int. J. Mol. Sci. 2021, 22(15), 7983; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157983
Received: 21 June 2021 / Revised: 22 July 2021 / Accepted: 22 July 2021 / Published: 26 July 2021
(This article belongs to the Special Issue Molecular Mechanisms of Cardioprotection)
Receptor-interacting protein kinase 3 (RIP3) is a convergence point of multiple signalling pathways, including necroptosis, inflammation and oxidative stress; however, it is completely unknown whether it underlies acute myocardial ischemia/reperfusion (I/R) injury. Langendorff-perfused rat hearts subjected to 30 min ischemia followed by 10 min reperfusion exhibited compromised cardiac function which was not abrogated by pharmacological intervention of RIP3 inhibition. An immunoblotting analysis revealed that the detrimental effects of I/R were unlikely mediated by necroptotic cell death, since neither the canonical RIP3–MLKL pathway (mixed lineage kinase-like pseudokinase) nor the proposed non-canonical molecular axes involving CaMKIIδ–mPTP (calcium/calmodulin-dependent protein kinase IIδ–mitochondrial permeability transition pore), PGAM5–Drp1 (phosphoglycerate mutase 5–dynamin-related protein 1) and JNK–BNIP3 (c-Jun N-terminal kinase–BCL2-interacting protein 3) were activated. Similarly, we found no evidence of the involvement of NLRP3 inflammasome signalling (NOD-, LRR- and pyrin domain-containing protein 3) in such injury. RIP3 inhibition prevented the plasma membrane rupture and delayed mPTP opening which was associated with the modulation of xanthin oxidase (XO) and manganese superoxide dismutase (MnSOD). Taken together, this is the first study indicating that RIP3 regulates early reperfusion injury via oxidative stress- and mitochondrial activity-related effects, rather than cell loss due to necroptosis. View Full-Text
Keywords: receptor-interacting protein kinase 3; necroptosis; myocardial ischemia/reperfusion receptor-interacting protein kinase 3; necroptosis; myocardial ischemia/reperfusion
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MDPI and ACS Style

Horvath, C.; Young, M.; Jarabicova, I.; Kindernay, L.; Ferenczyova, K.; Ravingerova, T.; Lewis, M.; Suleiman, M.S.; Adameova, A. Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling. Int. J. Mol. Sci. 2021, 22, 7983. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157983

AMA Style

Horvath C, Young M, Jarabicova I, Kindernay L, Ferenczyova K, Ravingerova T, Lewis M, Suleiman MS, Adameova A. Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling. International Journal of Molecular Sciences. 2021; 22(15):7983. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157983

Chicago/Turabian Style

Horvath, Csaba, Megan Young, Izabela Jarabicova, Lucia Kindernay, Kristina Ferenczyova, Tanya Ravingerova, Martin Lewis, M. S. Suleiman, and Adriana Adameova. 2021. "Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling" International Journal of Molecular Sciences 22, no. 15: 7983. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157983

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