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

Tadashi Yoshida, Ingeborg Friehs, Srinivas Mummidi, Pedro J. del Nido, Solange Addulnour-Nakhoul, Patrice Delafontaine, Anthony J. Valente, Bysani Chandrasekar

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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 4. weeks (mass/volume ratio: 1.7. ±. 0.11) and ventricular dilatation indicative of heart failure at 6. weeks (mass/volume ratio: 0.7. ±. 0.04). In concordance with this, fractional shortening was preserved at 4. weeks, but markedly attenuated at 6. weeks. 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, 1. Hz) 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.

Original languageEnglish (US)
Pages (from-to)141-151
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume75
DOIs
StatePublished - Oct 1 2014

Keywords

  • Cardiac failure
  • Cyclical stretch
  • Inflammation
  • Interleukins
  • Myocardial hypertrophy

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this