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04 February 2019 : Original article  

Autophagy and Oncosis/Necroptosis Are Enhanced in Cardiomyocytes from Heart Failure Patients

Giovanni Corsetti1ABCDEFG, Carol Chen-Scarabelli2ABCDEF, Claudia Romano3BCDF, Evasio Pasini4CD, Francesco S. Dioguardi5CE, Francesco Onorati6BD, Richard Knight7BCEF, Hemang Patel8B, Louis Saravolatz9CE, Giuseppe Faggian6BCE, Tiziano M. Scarabelli2ABCDEFG*

DOI: 10.12659/MSMBR.913436

Med Sci Monit Basic Res 2019; 25:33-44

Abstract

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 AND 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-κB (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-κB 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-κB pathway was associated with cell survival.

Keywords: Apoptosis, Autophagy, Heart Failure, Caspase 3, Middle Aged, Myocytes, Cardiac, NF-kappa B, Necrosis, Nuclear Pore Complex Proteins, RNA-Binding Proteins, Signal Transduction

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Medical Science Monitor Basic Research eISSN: 2325-4416
Medical Science Monitor Basic Research eISSN: 2325-4416