Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction.
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.
Abbate
Antonio
A
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
Salloum
Fadi N
FN
Vecile
Elena
E
Das
Anindita
A
Hoke
Nicholas N
NN
Straino
Stefania
S
Biondi-Zoccai
Giuseppe G L
GG
Houser
Jon-Erik
JE
Qureshi
Ian Z
IZ
Ownby
Evan D
ED
Gustini
Edoardo
E
Biasucci
Luigi M
LM
Severino
Anna
A
Capogrossi
Maurizio C
MC
Vetrovec
George W
GW
Crea
Filippo
F
Baldi
Alfonso
A
Kukreja
Rakesh C
RC
Dobrina
Aldo
A
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
D061945:Caspase Inhibitors; D053590:Interleukin 1 Receptor Antagonist Protein