Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling.
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.
['Horvath|Csaba|C|', 'Young|Megan|M|', 'Jarabicova|Izabela|I|', 'Kindernay|Lucia|L|', 'Ferenczyova|Kristina|K|0000-0001-9950-6287', 'Ravingerova|Tanya|T|0000-0002-8804-6964', 'Lewis|Martin|M|0000-0003-4410-5720', 'Suleiman|M Saadeh|MS|0000-0001-6080-480X', 'Adameova|Adriana|A|0000-0002-9803-043X']
D000818:Animals D002118:Calcium D020013:Calcium Signaling D008297:Male D008929:Mitochondria, Heart D015428:Myocardial Reperfusion Injury D009206:Myocardium D000079302:Necroptosis D051381:Rats D017208:Rats, Wistar D053422:Receptor-Interacting Protein Serine-Threonine Kinases
receptor-interacting protein kinase 3 necroptosis myocardial ischemia/reperfusion