IMR Press / RCM / Volume 23 / Issue 6 / DOI: 10.31083/j.rcm2306213
Open Access Original Research
Subacute Reperfusion in Ischemic Hearts: Study of Autophagy and its Possible Interconnection with Receptor-Interacting Protein Kinase 3
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1 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, 83232 Bratislava, Slovak Republic
2 Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 81438 Bratislava, Slovak Republic
3 Faculty of Health Sciences, Bristol Heart Institute, The Bristol Medical School, University of Bristol, BS8 Bristol, UK
*Correspondence: (Adriana Adameová)
Academic Editor: Gianluca Campo
Rev. Cardiovasc. Med. 2022, 23(6), 213;
Submitted: 1 April 2022 | Revised: 21 April 2022 | Accepted: 9 May 2022 | Published: 9 June 2022
(This article belongs to the Special Issue Myocardial infarction: unsolved issues and future options)
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Background: The role of cardiac autophagy during ischemia and reperfusion (I/R) remains controversial. Furthermore, whether this cell death during I/R is also interconnected with other cell damaging event, such as necroptosis, is insufficiently known. Thus, the aim of this study was to investigate possible links between autophagy and necroptosis in the hearts under conditions of acute I/R injury. Methods: Langendorff-perfused male Wistar rat hearts were subjected to 30-min global ischemia followed by 10-min reperfusion in the presence of either vehicle or a drug inhibiting the pro-necroptotic receptor-interacting protein kinase 3 (RIP3). Hemodynamic parameters and lactate dehydrogenase (LDH) release were measured to assess heart function and non-specific cell death due to the disruption of plasma membrane. Results: Immunoblot analysis of left ventricles revealed that early reperfusion suppressed the activation of autophagy as evidenced by the decreased protein expression of Beclin-1, pSer555-ULK1, pSer555-ULK1/ULK1 ratio, and LC3-II/LC3-I ratio. On the other hand, the molecular signalling responsible for autophagy inhibition did not appear to be affected in these I/R settings. RIP3 inhibition during reperfusion significantly mitigated the loss of the plasma membrane integrity but did not improve cardiac function. This pharmacological intervention targeting necroptosis-mediating protein decreased LC3-II expression in I/R hearts, suggesting some effect on autophagosome processing, but it did not significantly alter other signalling pathways involved in autophagy activation or inhibition. Conclusions: In summary, we showed for the first time that an early reperfusion phase does not promote autophagy and that there may be an interplay between pro-necroptotic protein RIP3 and autophagy with respect to the regulation of autophagosome processing.

myocardial ischemia/reperfusion injury
cell death
Fig. 1.
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