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(Circulation. 2001;104:I-308.)
© 2001 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Overexpression of Interleukin-1 Receptor Antagonist Provides Cardioprotection Against Ischemia-Reperfusion Injury Associated With Reduction in Apoptosis

Ken Suzuki, MD, PhD; Bari Murtuza, MA, FRCS; Ryszard T. Smolenski, MD, PhD; Ivan A. Sammut, PhD; Noriko Suzuki, MD; Yasufumi Kaneda, MD, PhD; Magdi H. Yacoub, FRS

Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College School of Medicine at the Heart Science Centre, Harefield Hospital, Middlesex, UK (K.S., B.M., R.T.S., I.A.S., N.S., M.H.Y.), and the Division of Gene Therapy Science, Osaka University, Osaka, Japan Y.K.).

Correspondence to Professor Sir Magdi H. Yacoub, Department of Cardiothoracic Surgery, Harefield Hospital, Harefield, Middlesex, UB9 6JH, UK. E-mail k.suzuki{at}ic.ac.uk

Background— Interleukin-1 (IL-1) plays a role in mediating acute inflammation during ischemia-reperfusion (I/R) injury in the heart, which leads to both necrosis and apoptosis of cardiomyocytes. IL-1 receptor antagonist (IL-1ra) is known to inhibit the effects of IL-1 and IL-1ß, resulting in attenuated inflammatory injury, and to protect cells from IL-1ß–induced apoptosis in vitro. We hypothesized that IL-1ra overexpression would provide cardioprotection by reducing inflammation-mediated myocardial damage including apoptosis after I/R injury in vivo.

Methods and Results— Rat hearts were transfected with human secreted–type IL-1ra gene by intracoronary infusion of Hemagglutinating Virus of Japan liposome and were heterotopically transplanted. IL-1ra overexpression in these hearts was confirmed by enzyme immunoassay and immunohistochemistry. Myocardial tolerance of the transplanted heart was evaluated with the use of a novel system in which the heart, existing within the recipient’s abdomen, was given 30 minutes of ischemia by left coronary artery occlusion and 24 hours of reperfusion. Consequently, infarct size was decreased in IL-1ra–transfected hearts compared with control-transfected ones (26.9±3.2% versus 46.2±3.0%, P=0.001), corresponding to lower myocardial myeloperoxidase activity (2.20±0.69 versus 6.82±1.19 U/g wet wt, P<0.001) and decreased neutrophil infiltration in histological study. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and DNA-laddering studies demonstrated that cardiomyocyte apoptosis was attenuated in IL-1ra–transfected hearts (21.4±3.3 versus 41.4±3.4%, P=0.002), correlating with reduced post I/R upregulation of Bax, Bak, and caspase-3.

Conclusions— IL-1ra introduced by gene transfection protected myocardium from I/R injury by attenuating the inflammatory response, which was associated with decreased apoptosis. This suggests a potentially important role of IL-1/IL-1ra in myocardial I/R injury and the value of IL-1ra-gene therapy for myocardial preservation.

Key Words: interleukins • inflammation • reperfusion • apoptosis • gene therapy