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

Abstract

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. After 7 days of daily intraperitoneal injections of 0.5 microg IL-18 in healthy mice, a 40% (P < 0.05) reduction in the LV maximal positive derivative, a 25% (P < 0.05) reduction in the LV maximal rate of pressure decay, and a 2.8-fold (P < 0.001) increase in the 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 microg/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.

Overexpression of Interleukin-18 Aggravates Cardiac Fibrosis and Diastolic Dysfunction in Fructose-Fed Rats

“…Overexpression of IL-18 has significantly aggravated cardiac fibrosis and the diastolic abnormalities but have no effects on systolic parameters. This is somewhat inconsistent with the results of Woldbaek et al (10), which showed daily administration of IL-18 in healthy mice causes LV myocardial systolic and diastolic dysfunction. The explanation for this discrepancy might lie in differences in Table 2.…”

“…Recent studies have shown that daily administration of IL-18 in healthy mice induces LV dysfunction and blunts β-adrenergic responsiveness to isoproterenol (10). Moreover, induction of myocardial hypertrophy by IL-18 indicates a role for this cytokine in myocardial remodeling.…”

Interleukin-18 knockout mice display maladaptive cardiac hypertrophy in response to pressure overload

“…The expression of IL-18 serves to amplify the inflammatory response by inducing cytokines, chemokines, and adhesion molecules in both immune and non-immune cells [10,11]. Recently it was shown that daily systemic IL-18 administration led to rapid LVH in the absence of hemodynamic stress demonstrating a role for IL-18 in cardiac growth [12]. In addition, IL-18 was shown to depress myocardial function in vivo and cardiomyocyte contractility in vitro [12,13].…”

“…Recently it was shown that daily systemic IL-18 administration led to rapid LVH in the absence of hemodynamic stress demonstrating a role for IL-18 in cardiac growth [12]. In addition, IL-18 was shown to depress myocardial function in vivo and cardiomyocyte contractility in vitro [12,13]. Finally, IL-18 has been demonstrated to be elevated in the serum of patients with LVH.…”

Interleukin-18 as a Therapeutic Target in Acute Myocardial Infarction and Heart Failure

“…ANP normally is expressed only early in development and its expression in adults is a sign of myocardial hypertrophy (57). Daily administration of IL-18 to healthy mice induces ANP expression in the heart, myocardial hypertrophy, and contractile dysfunction (58,59). IL-18 knockout (KO) mice subjected to pressure overload developed less hypertrophy, which is a key feature of the pathology, but also had worse contractile function (60).…”