Intracellular Function of Interleukin-1 Receptor Antagonist in Ischemic Cardiomyocytes

Elena Vecile, Aldo Dobrina, Fadi N. Salloum, Benjamin W. van Tassell, Antonella Falcione, Edoardo Gustini, Samuele Secchiero, Sergio Crovella, Gianfranco Sinagra, Nicoletta Finato, Martin J. Nicklin, Antonio Abbate

Research output: Contribution to journalArticle

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Abstract

Background: Loss of cardiac myocytes due to apoptosis is a relevant feature of ischemic heart disease. It has been described in infarct and peri-infarct regions of the myocardium in coronary syndromes and in ischemia-linked heart remodeling. Previous studies have provided protection against ischemia-induced cardiomyocyte apoptosis by the anti-inflammatory cytokine interleukin-1 receptor-antagonist (IL-1Ra). Mitochondria triggering of caspases plays a central role in ischemia-induced apoptosis. We examined the production of IL-1Ra in the ischemic heart and, based on dual intra/extracellular function of some other interleukins, we hypothesized that IL-1Ra may also directly inhibit mitochondria-activated caspases and cardiomyocyte apoptosis. Methodology/Principal Findings: Synthesis of IL-1Ra was evidenced in the hearts explanted from patients with ischemic heart disease. In the mouse ischemic heart and in a mouse cardiomyocyte cell line exposed to long-lasting hypoxia, IL-1Ra bound and inhibited mitochondria-activated caspases, whereas inhibition of caspase activation was not observed in the heart of mice lacking IL-1Ra (Il-1ra-/-) or in siRNA to IL-1Ra-interfered cells. An impressive 6-fold increase of hypoxia-induced apoptosis was observed in cells lacking IL-1Ra. IL-1Ra down-regulated cells were not protected against caspase activation and apoptosis by knocking down of the IL-1 receptor, confirming the intracellular, receptor-independent, anti-apoptotic function of IL-1Ra. Notably, the inhibitory effect of IL-1Ra was not influenced by enduring ischemic conditions in which previously described physiologic inhibitors of apoptosis are neutralized. Conclusions/Significance: These observations point to intracellular IL-1Ra as a critical mechanism of the cell self-protection against ischemia-induced apoptosis and suggest that this cytokine plays an important role in the remodeling of heart by promoting survival of cardiomyocytes in the ischemic regions.

Original languageEnglish
Article numbere53265
JournalPLoS One
Volume8
Issue number1
DOIs
Publication statusPublished - Jan 8 2013

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Interleukin-1 Receptors
interleukin-1
Cardiac Myocytes
antagonists
receptors
apoptosis
Apoptosis
caspases
Caspases
heart
ischemia
Mitochondria
Ischemia
mitochondria
infarction
myocardial ischemia
cardiomyocytes
Myocardial Ischemia
hypoxia
mice

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Vecile, E., Dobrina, A., Salloum, F. N., van Tassell, B. W., Falcione, A., Gustini, E., ... Abbate, A. (2013). Intracellular Function of Interleukin-1 Receptor Antagonist in Ischemic Cardiomyocytes. PLoS One, 8(1), [e53265]. https://doi.org/10.1371/journal.pone.0053265

Intracellular Function of Interleukin-1 Receptor Antagonist in Ischemic Cardiomyocytes. / Vecile, Elena; Dobrina, Aldo; Salloum, Fadi N.; van Tassell, Benjamin W.; Falcione, Antonella; Gustini, Edoardo; Secchiero, Samuele; Crovella, Sergio; Sinagra, Gianfranco; Finato, Nicoletta; Nicklin, Martin J.; Abbate, Antonio.

In: PLoS One, Vol. 8, No. 1, e53265, 08.01.2013.

Research output: Contribution to journalArticle

Vecile, E, Dobrina, A, Salloum, FN, van Tassell, BW, Falcione, A, Gustini, E, Secchiero, S, Crovella, S, Sinagra, G, Finato, N, Nicklin, MJ & Abbate, A 2013, 'Intracellular Function of Interleukin-1 Receptor Antagonist in Ischemic Cardiomyocytes', PLoS One, vol. 8, no. 1, e53265. https://doi.org/10.1371/journal.pone.0053265
Vecile E, Dobrina A, Salloum FN, van Tassell BW, Falcione A, Gustini E et al. Intracellular Function of Interleukin-1 Receptor Antagonist in Ischemic Cardiomyocytes. PLoS One. 2013 Jan 8;8(1). e53265. https://doi.org/10.1371/journal.pone.0053265
Vecile, Elena ; Dobrina, Aldo ; Salloum, Fadi N. ; van Tassell, Benjamin W. ; Falcione, Antonella ; Gustini, Edoardo ; Secchiero, Samuele ; Crovella, Sergio ; Sinagra, Gianfranco ; Finato, Nicoletta ; Nicklin, Martin J. ; Abbate, Antonio. / Intracellular Function of Interleukin-1 Receptor Antagonist in Ischemic Cardiomyocytes. In: PLoS One. 2013 ; Vol. 8, No. 1.
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