Mechanism of interleukin-1 receptor antagonist protection against myocardial ischaemia/reperfusion-induced injury.

BACKGROUND: New therapeutic targets are required for ischaemic heart disease; our study was designed to assess the theoretical foundation and experimental basis underlying the use of a new anticytokine agent, interleukin-1 receptor antagonist (IL-1ra), in this setting.

AIM: To investigate the cardioprotective properties of IL-1ra in terms of inhibition of apoptosis and improvement in systolic and diastolic functions of ischaemia/reperfusion (I/R)-injured cardiomyocytes, via a reduction in the inositol 1,4,5-trisphosphate (IP3) receptor-mediated Ca2+ overload induced by myocardial I/R injury.

METHODS: For in vivo animal experiments, 30 adult male Sprague Dawley rats were anaesthetized and randomized into sham, I/R, and IL-1ra+I/R groups (n=10 in each). All rats except the sham group were subjected to 30minutes of myocardial ischaemia, followed by 2hours of reperfusion. At a cellular level, healthy male Sprague Dawley rats under pentobarbital sodium anaesthesia underwent heart removal and isolation of individual ventricular cardiomyocytes using enzymatic hydrolysis, which were randomized into five groups: dimethyl sulphoxide; I/R; IL-1ra+I/R; 2-aminoethoxydiphenyl borate (2-APB)+I/R; and 2-APB+IL-1ra+I/R.

RESULTS: In the IL-1ra+I/R group, exacerbation of myocardial infarct size and I/R-induced injury was inhibited. At the cellular level, in the I/R group, peak shortening (% cell length) and maximal velocities of shortening and relengthening were significantly decreased and intracellular Ca2+ transient amplitude (measured as fura-fluorescence intensity change) was diminished by electric stimulation, with the decay time constant of Ca2+ transients increased versus the dimethyl sulphoxide group. Compared with the I/R group, statistically ameliorated variables were achieved in the IL-1ra+I/R, 2-APB+I/R and 2-APB+IL-1ra+I/R groups, with the 2-APB+IL-1ra+I/R group presenting more significant improvement, while there was no statistical difference between the IL-1ra+I/R and 2-APB+I/R groups.

CONCLUSIONS: The downregulation of IP3 receptors by IL-1ra attenuates Ca2+ overload and the systolic and diastolic dysfunctions of hypoxia/reoxygenation-injured cardiomyocytes, which contributes to inhibition of apoptosis in I/R-injured cardiomyocytes and reduction of myocardial infarct size in vivo.