on May 12, 2008
Published online before print May 12, 2008, doi: 10.1161/CIRCULATIONAHA.107.740233
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on September 17, 2007
From the Virginia Commonwealth University Pauley Heart Center, Richmond (A.A., F.N.S., A.D., N.N.H., S.S., J.-E.H., I.Z.Q., E.D.O., G.W.V., R.C.K.); Institute of Cardiology, Catholic University, Rome, Italy (A.A., L.M.B., A.S., F.C.); Department of Pathology and of Physiology, University of Trieste, Trieste, Italy (E.V., E.G., A.D.); Laboratorio di Patologia Vascolare, Istituto Dermopatico Immacolata–IRCCS, Rome, Italy (S.S., M.C.C.); Division of Cardiology, University of Turin, Turin, Italy (G.G.L.B.-Z.); and Department of Biochemistry and Biophysics "F. Cedrangolo," Section of Pathologic Anatomy, Second University of Naples, Naples, Italy (A.B.). * To whom correspondence should be addressed. E-mail: aabbate{at}mcvh-vcu.com.
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<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.
Accepted on March 31, 2008
Anakinra, a Recombinant Human Interleukin-1 Receptor Antagonist, Inhibits Apoptosis in Experimental Acute Myocardial Infarction
Antonio Abbate MD*,
Key words: apoptosis • cytokine • heart failure • ischemia • pharmacology • remodeling
Related Article:
Circulation 2008 117: 2567-2569.
This article has been cited by other articles:
 |
|
 |
|
  R. Klingenberg and G. K. Hansson Treating inflammation in atherosclerotic cardiovascular disease: emerging therapies Eur. Heart J., December 1, 2009; 30(23): 2838 - 2844. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Cao, Y. Hu, W. Wu, T. Ha, J. Kelley, C. Deng, Q. Chen, C. Li, J. Li, and Y. Li The TIR/BB-loop mimetic AS-1 protects the myocardium from ischaemia/reperfusion injury Cardiovasc Res, December 1, 2009; 84(3): 442 - 451. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I Ikonomidis, S Tzortzis, J Lekakis, I Paraskevaidis, I Andreadou, M Nikolaou, T Kaplanoglou, P Katsimbri, G Skarantavos, P Soucacos, et al. Lowering interleukin-1 activity with anakinra improves myocardial deformation in rheumatoid arthritis Heart, September 15, 2009; 95(18): 1502 - 1507. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. A. Turner, A. Das, P. Warburton, D. J. O'Regan, S. G. Ball, and K. E. Porter Interleukin-1{alpha} stimulates proinflammatory cytokine expression in human cardiac myofibroblasts Am J Physiol Heart Circ Physiol, September 1, 2009; 297(3): H1117 - H1127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Abbate, G. G. L. Biondi-Zoccai, B. W. Van Tassell, and A. Baldi Cellular preservation therapy in acute myocardial infarction Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H563 - H565. [Full Text] [PDF]
|
|
|
|
|
|
U. Landmesser, K. C. Wollert, and H. Drexler Potential novel pharmacological therapies for myocardial remodelling Cardiovasc Res, February 15, 2009; 81(3): 519 - 527. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. KAPOOR Anakinra and Its Rapidly Expanding Role in Management of Nonarthritic Systemic Disorders J Rheumatol, February 1, 2009; 36(2): 446 - 446. [Full Text] [PDF]
|
|