Different signalling in infarcted and non-infarcted areas of rat failing hearts: A role of necroptosis and inflammation
Different signalling in infarcted and non-infarcted areas of rat failing hearts: A role of necroptosis and inflammation
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DOI：
10.1111/jcmm.14536
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发表时间：
2019-07-21
影响因子：
5.3
通讯作者：
Adameova, Adriana
中科院分区：
文献类型：
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作者：
Lichy, Martin;Szobi, Adrian;Adameova, Adriana
在心力衰竭（HF）中已发现坏死性凋亡。在这项研究中，我们分别研究了梗死区和非梗死区的坏死性凋亡信号及其与HF主要特征的机制联系。通过左冠状动脉闭塞（60分钟）随后再灌注42天诱导大鼠梗死后HF。超声心动图评估心脏功能。分子信号传导和提出的机制（氧化应激，胶原沉积和炎症）进行了研究，在整个心脏和亚细胞组分时，适当的。在梗死后衰竭的心脏中，TNF和pSer 229-RIP 3水平在梗死和非梗死区域均显著增加。在梗死区检测到其细胞毒性下游分子p-MLKL，表明坏死性凋亡的执行。在非梗死区，尽管pSer 229-RIP 3增加，但p-MLKL既不存在于全细胞中，也不存在于已知与坏死性凋亡执行相关的细胞膜中。同样，增加膜脂质过氧化和NOX 2水平不太可能促进非梗死区的促坏死环境。胶原沉积和炎症性csp-1-IL-1 β轴在衰竭心脏的两个区域都是活跃的，而在梗死组织中更为明显。虽然凋亡蛋白在梗死和非梗死组织中表达不同，但发现凋亡起的作用不明显。p-MLKL驱动的坏死性凋亡和炎症，而仅炎症（无坏死性凋亡细胞死亡）似乎分别是衰竭心脏的梗死和非梗死区域中的纤维化愈合和进行性损伤的基础。pSer 229-RIP 3在两个HF区域中的上调表明，这种与坏死性凋亡和炎症相关的激酶可能在HF进展中起双重作用。
Necroptosis has been recognized in heart failure (HF). In this study, we investigated detailed necroptotic signalling in infarcted and non-infarcted areas separately and its mechanistic link with main features of HF. Post-infarction HF in rats was induced by left coronary occlusion (60 minutes) followed by 42-day reperfusion. Heart function was assessed echocardiographically. Molecular signalling and proposed mechanisms (oxidative stress, collagen deposition and inflammation) were investigated in whole hearts and in subcellular fractions when appropriate. In post-infarction failing hearts, TNF and pSer229-RIP3 levels were comparably increased in both infarcted and non-infarcted areas. Its cytotoxic downstream molecule p-MLKL, indicating necroptosis execution, was detected in infarcted area. In non-infarcted area, despite increased pSer229-RIP3, p-MLKL was present in neither whole cells nor the cell membrane known to be associated with necroptosis execution. Likewise, increased membrane lipoperoxidation and NOX2 levels unlikely promoted pro-necroptotic environment in non-infarcted area. Collagen deposition and the inflammatory csp-1-IL-1 beta axis were active in both areas of failing hearts, while being more pronounced in infarcted tissue. Although apoptotic proteins were differently expressed in infarcted and non-infarcted tissue, apoptosis was found to play an insignificant role. p-MLKL-driven necroptosis and inflammation while inflammation only (without necroptotic cell death) seem to underlie fibrotic healing and progressive injury in infarcted and non-infarcted areas of failing hearts, respectively. Upregulation of pSer229-RIP3 in both HF areas suggests that this kinase, associated with both necroptosis and inflammation, is likely to play a dual role in HF progression.