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J Mol Cell Cardiol. 2014 Oct;75:141-51. doi: 10.1016/j.yjmcc.2014.07.007. Epub 2014 Aug 7.

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 information

1
Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, USA.
2
Department of Cardiac Surgery, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
3
South Texas Veterans Health Care System and Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA.
4
Department of Medicine-Gastroenterology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, USA.
5
Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, USA; Research Service, Southeast Louisiana Veterans Health Care System, New Orleans, LA 70161, USA. Electronic address: bchandra@tulane.edu.

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.

KEYWORDS:

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

PMID:
25108227
PMCID:
PMC4157969
DOI:
10.1016/j.yjmcc.2014.07.007
[Indexed for MEDLINE]
Free PMC Article

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