Autophagy and Oncosis/Necroptosis Are Enhanced in Cardiomyocytes from Heart Failure Patients
Autophagy and Oncosis/Necroptosis Are Enhanced in Cardiomyocytes from Heart Failure Patients
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DOI：
10.12659/msmbr.913436
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发表时间：
2019-02-04
影响因子：
2.8
通讯作者：
Scarabelli, Tiziano M.
中科院分区：
文献类型：
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作者：
Corsetti, Giovanni;Chen-Scarabelli, Carol;Scarabelli, Tiziano M.
背景：虽然自噬最初被描述为一种生存机制，但目前尚不清楚自噬是否以及在多大程度上与心力衰竭终末期有关。在这里，我们研究了顽固性心力衰竭患者自噬的大小和进化。材料/方法：选取22例接受心脏移植的缺血性心肌病和特发性扩张型心肌病患者的心肌样本。11例非心脏原因死亡患者的心脏作为对照样本。采用单克隆微管相关蛋白轻链3 (LC3)- ii抗体进行免疫染色，采用TUNEL（末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记法）双染色和补体9 （C9）免疫染色分别评估自噬与凋亡和肿瘤的关系。此外，通过免疫组织化学评估几种坏死标志物，包括RIP1和RIP3（受体相互作用蛋白激酶1和3），抗c3（裂解caspase-3）和抗nf -kappa B（活化B细胞的核因子kappa轻链增强剂）。结果：在8.7 +/- 1.6%的心力衰竭患者心脏样本和1.2 +/- 0.3%的对照患者心脏样本中检测到抗lc3 - ii染色。液泡的形成始于一个核极，然后变成双极并涉及细胞质。随后，自噬过程也扩展到细胞核，细胞核经历了渐进的空泡化和解体，呈现出独特的“草莓样外观”。具有广泛液泡形成的肌细胞表现出核变性，这与TUNEL、C3、C9、RIP1和RIP3阳性染色有关。相反，液泡形成较少的肌细胞显示RIP1和NF-kappa B阳性染色，但其他细胞死亡标志物未呈阳性。结论：自噬在终末期心力衰竭及其进展中广泛存在，导致继发性细胞死亡，肿瘤和坏死坏死的发生超过细胞凋亡。相反，RIP1/NF-kappa B通路的激活与细胞存活有关。
Background: Although originally described as a survival mechanism, it is unknown whether and to what extent autophagy is implicated in the terminal stages of heart failure. Here, we studied magnitude and evolution of autophagy in patients with intractable heart failure.Material/Methods: Myocardial samples were obtained from 22 patients with ischemic cardiomyopathy and idiopathic dilated cardiomyopathy who were undergoing cardiac transplantation. Hearts from 11 patients who died from non-cardiac causes were used as control samples. Autophagy was evaluated by immunostaining with a monoclonal microtubule associated protein light chain 3 (LC3)-II antibody, while the relationship of autophagy with apoptosis and oncosis was assessed by double staining with TUNEL (terminal deoxynucleotidyl transferase - mediated deoxyuridine triphosphate nick end labeling) assay and complement 9 (C9) immunological staining, respectively. In addition, several necroptotic markers, including RIP1 and RIP3 (receptor interacting protein kinase 1 and 3), anti-C3 (cleaved-caspase-3), and anti-NF-kappa B (nuclear factor kappa-light-chain-enhancer of activated B cells) were assessed by immunohistochemistry.Results: Anti-LC3-II staining was detected in 8.7 +/- 1.6% of the heart failure patient heart samples and in 1.2 +/- 0.3% of control patient heart samples. Vacuole formation started at one nuclear pole, before becoming bipolar and involving the cytosol. Subsequently, the autophagic process extended also to the nuclei, which underwent a progressive vacuolization and disintegration, assuming a peculiar "strawberry like appearance". Myocytes with extensive vacuole formation exhibited nuclear degeneration, which was associated with TUNEL, C3, C9, RIP1, and RIP3 positive staining. Conversely, myocytes with less extensive vacuole formation showed RIP1 and NF-kappa B positive staining, though not positivity for other cell death markers.Conclusions: Autophagy was extensively detected in end-stage heart failure and its progression, resulted in secondary cell death, with occurrence of oncosis and necroptosis exceeding that of apoptosis. Conversely, activation of the RIP1/NF-kappa B pathway was associated with cell survival.