Abstract 298: Low-dose Interleukin-18 is Necessary to Adapt to Pressure Overload in Mice

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Background: We previously reported that circulatory Interleukin-18 (IL-18) level elevates in heart failure (HF) patients. However, the roles of circulatory IL-18 in HF have not been fully elucidated. Continuous infusion of IL-18 induces cardiomyocyte hypertrophy and fibrosis, whereas IL-18 null mice were fragile to pressure overload. We hypothesized that systemic (circulatory) and local (cardiac) IL-18 have distinct effects on HF and cardiac remodeling.

Purpose: The purpose of this study was to elucidate the role of circulatory IL-18 in adaptation to pressure overload in IL-18 null mice.

Methods: Wild type (WT) mice and IL-18 null (IL-18-/-) were subjected to transaortic constriction (TAC). Sequential serum IL-18 levels myocardial IL-18 mRNA expressions were determined by ELISA and qRT-PCR in WT mice. After two week of TAC, IL-18 null mice were administered either (IP) saline or recombinant IL-18 intraperitoneally (10ng/20g every other day). Cardiac function was assessed by transthoracic echocardiography. Two weeks after TAC, myocardial samples were obtained. Haematoxylin and eosin stained sections and Masson’s trichrome staining sections were prepared.

Results: IL-18 concentration in serum and IL-18 expression in myocardial tissue increased gradually after TAC in WT mice. Forty-seven % (7/15) of TAC-operated IL-18-/- mice and 12% (2/17) of TAC-operated WT mice died of heart failure by 14days. TAC-operated IL-18-/- mice exhibited more severe left ventricular (LV) remodeling, characterized by cardiomyocyte hypertrophy, extensive interstitial fibrosis and elevation of fetal gene expressions compared with TAC-WT mice. Recombinant IL-18 given intraperitoneally improved the survival rate to 100% (10/10) following TAC operation in IL-18-/- mice. Furthermore, exogenous IL-18 administration suppressed ventricular ANP mRNA expression and myocardial cross-sectional area enlargement to non-TAC-operated level, whereas LV enlargement and contractile dysfunction were only partially suppressed in IL-18-/- mice following TAC.

Conclusions: Circulatory IL-18 exerts opposing effects on cardiac hypertrophy under pressure-overload. IL-18 produced in the heart may have an effect such as preserving contractile function.

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