title: 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.
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.
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Cardiac Surgery, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Friehs
authors.affiliation: South Texas Veterans Health Care System and Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Mummidi
authors.affiliation: Department of Cardiac Surgery, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: del Nido
authors.affiliation: 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.
authors.forename: Solange
authors.initials: S
authors.lastname: Addulnour-Nakhoul
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Patrice
authors.initials: P
authors.lastname: Delafontaine
authors.affiliation: Department of Cardiac Surgery, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.affiliation: 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.
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011312:Pressure; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D053724:Receptors, Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D013314:Stress, Mechanical; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014463:Ultrasonography
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D012333:RNA, Messenger; D053724:Receptors, Interleukin-18; D014409:Tumor Necrosis Factor-alpha; C118370:interleukin-18 binding protein
keywords: Cardiac failure; Cyclical stretch; Inflammation; Interleukins; Myocardial hypertrophy
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