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Am J Physiol Heart Circ Physiol (April 8, 2005). doi:10.1152/ajpheart.01179.2004
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Submitted on November 23, 2004
Accepted on April 6, 2005

Daily administration of interleukin-18 causes myocardial dysfunction in healthy mice

Per R Woldbaek1*, Jorn B Sande2, Taevje A Stromme2, Per K Lunde2, Srdjan Djurovic3, Torstein Lyberg4, Geir Christensen2, and Theis Tonnessen1

1 Ullevaal University Hospital, Institute for Experimental Medical Research, Oslo, Norway; Ullevaal University Hospital, Department of Cardiothoracic Surgery, Oslo, Norway
2 Ullevaal University Hospital, Institute for Experimental Medical Research, Oslo, Norway
3 Ullevaal University Hospital, Institute for Medical Genetics, Oslo, Norway
4 Ullevaal University Hospital, Center for Clinical Research, Oslo, Norway

* To whom correspondence should be addressed. E-mail: pewo{at}uus.no.

Although increased levels of circulating interleukin (IL)-18 have been demonstrated in patients with cardiovascular diseases, the functional consequences of chronically increased circulating IL-18 with respect to myocardial function have not been defined. Thus, we aimed to examine the effects of chronic IL-18 exposure on left ventricular (LV) function in healthy mice. Moreover, to clarify whether IL-18 has direct effects on the cardiomyocyte we examined effects of IL-18 on cardiomyocytes in vitro. Following 7 days of daily intraperitoneal injections of 0.5 µg IL-18 in healthy mice, a 40 % (p<0.05) reduction in LV+dP/dt, a 25 % (p<0.05) reduction in LV-dP/dt and a 2.8-fold (p<0.001) increase in LV end-diastolic pressure were measured, consistent with myocardial dysfunction. Furthermore, we measured a 75 % (p<0.05) reduction in {beta}-adrenergic responsiveness to isoproterenol. IL-18 induced myocardial hypertrophy, and there was a 2.9-fold increase (p<0.05) in atrial natriuretic peptide mRNA expression in the LV myocardium. In vitro examinations of isolated adult rat cardiomyocytes being stimulated with IL-18 (0.1 µg/ml) exhibited an increase in peak Ca2+ transients (p<0.05) and in diastolic Ca2+ concentrations (p<0.05). In conclusion, this study shows that daily administration of IL-18 in healthy mice causes LV myocardial dysfunction and blunted {beta}-adrenergic responsiveness to isoproterenol. A direct effect of IL-18 on the cardiomyocyte in vitro was demonstrated suggesting that IL-18 reduces the responsiveness of the myofilaments to Ca2+. Finally, induction of myocardial hypertrophy by IL-18 indicates a role for this cytokine in myocardial remodeling.




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