Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction

Antonio Abbate, Fadi N. Salloum, Elena Vecile, Anindita Das, Nicholas N. Hoke, Stefania Straino, G. L. Giuseppe, [No Value] Biondi-Zoccai, Jon Erik Houser, Ian Z. Qureshi, Evan D. Ownby, Edoardo Gustini, Luigi M. Biasucci, Anna Severino, Maurizio C. Capogrossi, George W. Vetrovec, Filippo Crea, Alfonso Baldi, Rakesh C. Kukreja, Aldo Dobrina

Research output: Contribution to journalArticle

Abstract

Background Experimental interleukin-1 receptor antagonist gene overexpression has shown that interleukin-1 receptor antagonist is cardioprotective during global cardiac ischemia. The aim of the present study was to test the impact of an exogenous recombinant human interleukin-1 receptor antagonist (anakinra) in experimental acute myocardial infarction. Methods and Results Two animal studies were conducted: one of immediate anakinra administration during ischemia in the mouse and one of delayed anakinra administration 24 hours after ischemia in the rat. Seventy-eight Institute of Cancer Research mice and 20 Wistar rats underwent surgical coronary artery ligation (or sham operation) and were treated with either anakinra 1 mg/kg or NaCl 0.9% (saline). Treatment was administered during surgery and then daily for 6 doses in the mice and starting on day 2 daily for 5 doses in the rats. Twenty-eight mice underwent infarct size assessment 24 hours after surgery, 6 saline-treated mice and 22 mice treated with increasing doses of anakinra (1 mg/kg [n=6], 10 mg/kg [n=6], and 100 mg/kg [n=10]); 6 mice were euthanized at 7 days for protein expression analysis. The remaining animals underwent transthoracic echocardiography before surgery and 7 days later just before death. Cardiomyocyte apoptosis was measured in the peri-infarct regions. The antiapoptotic effect of anakinra was tested in a primary rat cardiomyocyte culture during simulated ischemia and in vitro on caspase-1 and-9 activities. At 7 days, 15 of the 16 mice (94%) treated with anakinra were alive versus 11 of the 20 mice (55%) treated with saline (P=0.013). No differences in infarct size at 24 hours compared with saline were observed with the 1- and 10-mg/kg doses, whereas a 13% reduction in infarct size was found with the 100-mg/kg dose (P=0.015). Treatment with anakinra was associated with a significant reduction in cardiomyocyte apoptosis in both the immediate and delayed treatment groups (3.1±0.2% versus 0.5±0.3% [P

Original languageEnglish
Pages (from-to)2670-2683
Number of pages14
JournalCirculation
Volume117
Issue number20
DOIs
Publication statusPublished - May 20 2008

Keywords

  • Apoptosis
  • Cytokine
  • Heart failure
  • Ischemia
  • Pharmacology
  • Remodeling

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine
  • Physiology

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  • Cite this

    Abbate, A., Salloum, F. N., Vecile, E., Das, A., Hoke, N. N., Straino, S., Giuseppe, G. L., Biondi-Zoccai, N. V., Houser, J. E., Qureshi, I. Z., Ownby, E. D., Gustini, E., Biasucci, L. M., Severino, A., Capogrossi, M. C., Vetrovec, G. W., Crea, F., Baldi, A., Kukreja, R. C., & Dobrina, A. (2008). Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation, 117(20), 2670-2683. https://doi.org/10.1161/CIRCULATIONAHA.107.740233