Relevance of necroptosis in the hearts subjected to acute versus chronic ischemia/reperfusion injury
Relevance of necroptosis in the hearts subjected to acute versus chronic ischemia/reperfusion injury
复制标题
急性与慢性缺血/再灌注损伤心脏坏死性凋亡的相关性
DOI：
10.1093/cvr/cvac066.053
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发表时间：
2022
影响因子：
10.8
通讯作者：
Horvath C
中科院分区：
文献类型：
--
作者：
Horvath C
资金来源类型：公共机构。主要资金来源：Slovak Research and Development Clinical Research理事会GrantNecroptosis是一种依赖于受体相互作用蛋白激酶3（RIP 3）和混合谱系域激酶域样假激酶（MLKL）活性的坏死样程序性细胞死亡模式，在介导心肌缺血/再灌注损伤中发挥重要作用。然而，在短期和长期再灌注下，坏死性凋亡在多大程度上导致这种损伤尚未详细评估。在Wistar大鼠心脏中，经过30分钟的全身缺血，然后经过10分钟的急性再灌注期，心脏功能受损，主要坏死标志物的蛋白表达没有变化（pThr231/Ser232-RIP3，MLKL）。涉及Ca 2 +/钙调蛋白依赖性蛋白激酶II-线粒体渗透性转换孔的坏死性凋亡非经典途径（CaMKII-mPTP）或磷酸甘油酸酯-β 5-动力蛋白相关蛋白1（PGAM 5-Drp 1）轴不太可能受到如此短的再灌注的影响。与此相反，心脏缺血30分钟，随后延长40分钟的再灌注期表现出恶化的血流动力学参数，伴随着RIP 3，pSer 229-RIP 3和MLKL的水平增加。此外，该再灌注期诱导MLKL易位至质膜，表明坏死性凋亡执行，导致非常可能的细胞破坏。类似地，由较高水平的经典途径蛋白质证明的活化的坏死性凋亡已被认为有助于梗死后心力衰竭（30分钟缺血，42天再灌注）的发病机制。总的来说，这些研究结果表明，短期再灌注似乎不足以诱导心脏坏死性凋亡，需要在较长的再灌注阶段激活的分子机制来促进坏死性凋亡细胞死亡。因此，抑制坏死性凋亡可能是慢性心肌缺血/再灌注损伤的心脏保护策略，而不是急性心肌缺血/再灌注损伤。霍瓦特）
Funding AcknowledgementsType of funding sources: Public Institution(s). Main funding source(s): Slovak Research and Development AgencyMedical Research Council GrantNecroptosis, a necrosis-like programmed cell death modality dependent on the activity of receptor-interacting protein kinase 3 (RIP3) and mixed lineage domain kinase domain-like pseudokinase (MLKL), plays a prominent role in mediating myocardial ischemia/reperfusion injury. However, the extent to which necroptosis contributes to such damage under short and long reperfusion has not been evaluated in detail. In Wistar rat hearts, subjected to global 30-min ischemia followed by an acute 10-min reperfusion period, with compromised cardiac function, no changes in the protein expression of the main necroptotic markers (pThr231/Ser232-RIP3, MLKL) were found. Likewise, the non-canonical pathways of necroptosis involving Ca2+/calmodulin dependent protein kinase II–mitochondrial permeability transition pore (CaMKII–mPTP) or phosphoglycerate mutase 5–dynamin-related protein 1 (PGAM5–Drp1) axes were unlikely affected by such short reperfusion. In contrast, hearts subjected to global 30-min ischemia followed by a prolonged 40-min reperfusion period exhibited worsened hemodynamic parameters what was accompanied by the increased levels of RIP3, pSer229-RIP3 and MLKL. Moreover, this reperfusion period induced MLKL translocation to the plasma membrane, indicating necroptosis execution with resultant very likely cell disruption. Similarly, activated necroptosis, evidenced by the higher levels of proteins of the canonical pathway, has been suggested to contribute to the pathogenesis of post-infarction heart failure (30-min ischemia, 42-day reperfusion). Collectively, these findings suggest that short reperfusion seems to be insufficient to induce necroptosis in the heart and the molecular mechanisms being activated during the longer reperfusion phase are needed to promote necroptotic cell dying. Therefore, inhibition of necroptosis might represent a cardioprotective strategy in the settings of chronic, but not acute myocardial ischemia/reperfusion injury.Abstract Picture 1 (C. Horvath)