Abstract 15168: Interleukin-18 Enhances Mitochondrial Function in Pressure Overload through AMP-activated Protein Kinase Activation
Introduction: We have reported that serum Interleukin-18 (IL-18) concentrations increased according to worsening heart failure (HF) functional class. However, the pathological roles of serum IL-18 elevation in HF have not been fully elucidated. The purpose of this study was to elucidate the role of IL-18 in adaptation to pressure overload in IL-18 null mice.
Hypothesis: We hypothesized that IL-18 plays a key role in pressure overload-induced hypertrophic responses by enhancing mitochondrial function.
Methods: Ten-week-old male C57BL6/J-background wild type (WT) mice and C57BL6/J-background IL-18 null (IL-18-/-) were subjected to transaortic constriction (TAC). Cardiac function was assessed by transthoracic echocardiography every week. Two weeks after TAC, myocardial samples were obtained. Detection of cardiac gene expressions by q-RT PCR and quantification of phospho-proteins by western blot were performed. An AMPK activator (AICAR 100mg/kg,) was given intraperitoneally everyday after TAC procedure.
Results: IL-18 concentration in serum and IL-18 expression in myocardial tissue increased gradually after TAC in WT mice. Forty-seven % of TAC-operated IL-18-/- mice and 12% of TAC-operated WT mice died of heart failure by 14 days. TAC-operated IL-18-/- mice exhibited severer left ventricular (LV) remodeling, characterized by cardiomyocyte hypertrophy, extensive interstitial fibrosis, and elevation of fetal gene expressions compared with TAC- operated WT mice. Phosphorylation at threonine 183 of AMP-activated protein kinase (AMPK), and mitochondrial transcription factor A (TFAM) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) mRNA expression were significantly decreased in the heart of TAC-operated IL-18-/- mice compared to TAC-operated WT mice. AICAR administration improved the survival rate of TAC-operated in IL-18-/- mice to 100%. Furthermore, AICAR administration suppressed LV remodeling, and restored TFAM and PGC1α mRNA expression.
Conclusions: IL-18 enhances mitochondrial function in pressure overload through AMP-activated protein kinase activation.
Author Disclosures: T. Iwasaku: None. S. Hirotani: None. A. Eguchi: None. Y. Okuhara: None. D. Morisawa: None. M. Oboshi: None. H. Sawada: None. Y. Naito: None. T. Mano: None. T. Masuyama: None.
- © 2014 by American Heart Association, Inc.