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J Transl Med. 2017 Apr 28;15(1):86. doi: 10.1186/s12967-017-1189-5.

Analysis of necroptotic proteins in failing human hearts.

Author information

1
Department of Pharmacology & Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 832 32, Bratislava, Slovakia.
2
Department of Heart Failure & Transplantation, The National Institute of Cardiovascular Diseases, Bratislava, Slovakia.
3
Department of Pharmacology & Pharmacotherapy, Semmelweis University, Budapest, Hungary.
4
Institute of Cardiology, Warsaw, Poland.
5
Clinic of Heart Surgery, The National Institute of Cardiovascular Diseases, Bratislava, Slovakia.
6
Department of Pharmacology & Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, 832 32, Bratislava, Slovakia. adameova@fpharm.uniba.sk.

Abstract

BACKGROUND:

Cell loss and subsequent deterioration of contractile function are hallmarks of chronic heart failure (HF). While apoptosis has been investigated as a participant in the progression of HF, it is unlikely that it accounts for the total amount of non-functional tissue. In addition, there is evidence for the presence of necrotic cardiomyocytes in HF. Therefore, the objective of this study was to investigate the necroptotic proteins regulating necroptosis, a form of programmed necrosis, and thereby assess its potential role in human end-stage HF.

METHODS:

Left ventricular samples of healthy controls (C) and patients with end-stage HF due to myocardial infarction (CAD) or dilated cardiomyopathy (DCM) were studied. Immunoblotting for necroptotic and apoptotic markers was performed. Triton X-114 fractionated samples were analyzed to study differences in subcellular localization.

RESULTS:

Elevated expression of RIP1 (receptor-interacting protein), pSer227-RIP3 and its total levels were observed in HF groups compared to controls. On the other hand, caspase-8 expression, a proapoptotic protease negatively regulating necroptosis, was downregulated suggesting activation of necroptosis signaling. Total mixed-lineage kinase domain-like protein (MLKL) expression did not differ among the groups; however, active cytotoxic forms of MLKL were present in all HF samples while they were expressed at almost undetectable levels in controls. Interestingly, pThr357-MLKL unlike pSer358-MLKL, was higher in DCM than CAD. In HF, the subcellular localization of both RIP3 and pThr357-MLKL was consistent with activation of necroptosis signaling. Expression of main apoptotic markers has not indicated importance of apoptosis.

CONCLUSIONS:

This is the first evidence showing that human HF of CAD or DCM etiology is positive for markers of necroptosis which may be involved in the development of HF.

KEYWORDS:

Cell death; Heart failure; MLKL; Necroptosis

PMID:
28454582
PMCID:
PMC5410070
DOI:
10.1186/s12967-017-1189-5
[Indexed for MEDLINE]
Free PMC Article

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