1. Pressure overload induces IL-18 and IL-18R expression, but markedly suppresses IL-18BP expression in a rabbit model. IL-18 potentiates TNF-α-induced cardiomyocyte death.
- Author
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Yoshida T, Friehs I, Mummidi S, del Nido PJ, Addulnour-Nakhoul S, Delafontaine P, Valente AJ, and Chandrasekar B
- Subjects
- Animals, Cardiomegaly diagnostic imaging, Cardiomegaly pathology, Cell Death drug effects, Disease Models, Animal, Endothelial Cells drug effects, Endothelial Cells pathology, Heart Failure metabolism, Humans, Intercellular Signaling Peptides and Proteins genetics, Interleukin-18 genetics, Male, Molecular Sequence Data, Myocytes, Cardiac drug effects, Myocytes, Cardiac metabolism, Pressure, RNA, Messenger genetics, RNA, Messenger metabolism, Rabbits, Receptors, Interleukin-18 genetics, Stress, Mechanical, Ultrasonography, Intercellular Signaling Peptides and Proteins metabolism, Interleukin-18 metabolism, Myocytes, Cardiac pathology, Receptors, Interleukin-18 metabolism, Tumor Necrosis Factor-alpha pharmacology
- Abstract
Recurrent or sustained inflammation plays a causal role in the development and progression of left ventricular hypertrophy (LVH) and its transition to failure. Interleukin (IL)-18 is a potent pro-hypertrophic inflammatory cytokine. We report that induction of pressure overload in the rabbit, by constriction of the descending thoracic aorta induces compensatory hypertrophy at 4weeks (mass/volume ratio: 1.7±0.11) and ventricular dilatation indicative of heart failure at 6weeks (mass/volume ratio: 0.7±0.04). In concordance with this, fractional shortening was preserved at 4weeks, but markedly attenuated at 6weeks. We cloned rabbit IL-18, IL-18Rα, IL-18Rβ, and IL-18 binding protein (IL-18BP) cDNA, and show that pressure overload, while enhancing IL-18 and IL-18R expression in hypertrophied and failing hearts, markedly attenuated the level of expression of the endogenous IL-18 antagonist IL-18BP. Cyclical mechanical stretch (10% cyclic equibiaxial stretch, 1Hz) induced hypertrophy of primary rabbit cardiomyocytes in vitro and enhanced ANP, IL-18, and IL-18Rα expression. Further, treatment with rhIL-18 induced its own expression and that of IL-18Rα via AP-1 activation, and induced cardiomyocyte hypertrophy in part via PI3K/Akt/GATA4 signaling. In contrast, IL-18 potentiated TNF-α-induced cardiomyocyte death, and by itself induced cardiac endothelial cell death. These results demonstrate that pressure overload is associated with enhanced IL-18 and its receptor expression in hypertrophied and failingrabbit hearts. Since IL-18BP expression is markedly inhibited, our results indicate a positive amplification in IL-18 proinflammatory signaling during pressure overload, and suggest IL-18 as a potential therapeutic target in pathological hypertrophy and cardiac failure., (Published by Elsevier Ltd.)
- Published
- 2014
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