Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling.
Inhibition of Cardiac RIP3 Mitigates Early Reperfusion Injury and Calcium-Induced Mitochondrial Swelling without Altering Necroptotic Signalling.
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抑制心脏RIP3可减轻早期再灌注损伤和钙诱导的线粒体肿胀，而不改变坏死信号。
DOI：
10.3390/ijms22157983
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发表时间：
2021-07-26
影响因子：
5.6
通讯作者：
Adameova A
中科院分区：
文献类型：
--
作者：
Horvath C;Young M;Jarabicova I;Kindernay L;Ferenczyova K;Ravingerova T;Lewis M;Suleiman MS;Adameova A
受体相互作用蛋白激酶 3 (RIP3) 是多种信号通路的汇聚点，包括坏死性凋亡、炎症和氧化应激；然而，尚不清楚它是否是急性心肌缺血/再灌注（I/R）损伤的基础。 Langendorff 灌注的大鼠心脏经过 30 分钟缺血，然后再灌注 10 分钟，表现出心脏功能受损，而抑制 RIP3 的药物干预并不能消除这种受损的心脏功能。免疫印迹分析显示，I/R 的有害影响不太可能是由坏死性细胞死亡介导的，因为规范的 RIP3-MLKL 通路（混合谱系激酶样假激酶）和涉及 CaMKIIδ-mPTP（钙/钙调蛋白依赖性蛋白激酶 IIδ-线粒体通透性转换孔）、PGAM5-Drp1（磷酸甘油酸变位酶）的非规范分子轴均不存在。 5-动力相关蛋白 1) 和 JNK-BNIP3（c-Jun N 末端激酶-BCL2 相互作用蛋白 3）被激活。同样，我们没有发现任何证据表明 NLRP3 炎性体信号传导（NOD、LRR 和 Pyrin 结构域蛋白 3）参与此类损伤。 RIP3 抑制可防止质膜破裂并延迟 mPTP 打开，这与黄质氧化酶 (XO) 和锰超氧化物歧化酶 (MnSOD) 的调节有关。总而言之，这是第一项表明 RIP3 通过氧化应激和线粒体活性相关效应调节早期再灌注损伤的研究，而不是通过坏死性凋亡引起的细胞损失。
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.
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影响因子：
5
作者：
Feng N;Anderson ME
通讯作者：
Anderson ME
影响因子：
3.4
作者：
Lim, S. Y.;Davidson, S. M.;Mocanu, M. M.;Yellon, D. M.;Smith, C. C. T.
通讯作者：
Smith, C. C. T.
影响因子：
4.3
作者：
Horvath，C.;Szobi，A.;Adameova，A.
通讯作者：
Adameova，A.
影响因子：
5.3
作者：
Lichy, Martin;Szobi, Adrian;Adameova, Adriana
通讯作者：
Adameova, Adriana
JNK信号通路和RIPK3/AIF在坏死性凋亡介导的大鼠全脑缺血/再灌注损伤中的调控
影响因子：
5.3
作者：
Hu, Wenjie;Wu, Xiaodong;Xu, Yang
通讯作者：
Xu, Yang