title: Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction.
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.
  
  
  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<0.001] and 4.2+/-0.4% versus 1.1+/-0.2% [P<0.001], respectively). Compared with saline-treated animals, anakinra-treated mice and rats showed signs of more favorable ventricular remodeling. In vitro, anakinra significantly prevented apoptosis induced by simulated ischemia and inhibited caspase-1 and -9 activities.
  
  
  CONCLUSIONS
  Administration of anakinra within 24 hours of acute myocardial infarction significantly ameliorates the remodeling process by inhibiting cardiomyocyte apoptosis in 2 different experimental animal models of AMI. This may open the door for using anakinra to prevent postischemic cardiac remodeling and heart failure.
authors.affiliation: Division of Cardiology/VCU Pauley Heart Center, Virginia Commonwealth University, 1200 E Broad St, West Hospital, 10th Floor, East Wing, Room 1041, PO Box 980281, Richmond, VA 23298-0281, USA. aabbate@mcvh-vcu.com
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.forename: Elena
authors.initials: E
authors.lastname: Vecile
authors.forename: Anindita
authors.initials: A
authors.lastname: Das
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Hoke
authors.forename: Stefania
authors.initials: S
authors.lastname: Straino
authors.forename: Giuseppe G L
authors.initials: GG
authors.lastname: Biondi-Zoccai
authors.forename: Jon-Erik
authors.initials: JE
authors.lastname: Houser
authors.forename: Ian Z
authors.initials: IZ
authors.lastname: Qureshi
authors.forename: Evan D
authors.initials: ED
authors.lastname: Ownby
authors.forename: Edoardo
authors.initials: E
authors.lastname: Gustini
authors.forename: Luigi M
authors.initials: LM
authors.lastname: Biasucci
authors.forename: Anna
authors.initials: A
authors.lastname: Severino
authors.forename: Maurizio C
authors.initials: MC
authors.lastname: Capogrossi
authors.forename: George W
authors.initials: GW
authors.lastname: Vetrovec
authors.forename: Filippo
authors.initials: F
authors.lastname: Crea
authors.forename: Alfonso
authors.initials: A
authors.lastname: Baldi
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
authors.forename: Aldo
authors.initials: A
authors.lastname: Dobrina
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D004195:Disease Models, Animal; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D061945:Caspase Inhibitors; D053590:Interleukin 1 Receptor Antagonist Protein