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Pressure overload amplifies IL‐18 signaling in a rabbit model of myocardial hypertrophy and failure
Author(s) -
Yoshida Tadashi,
Srinivas Mummidi,
Friehs Ingeborg,
Nido Pedro J.,
Somanveen,
Valente Anthony J.,
Chandrasekar Bysani
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1085.7
Subject(s) - pressure overload , muscle hypertrophy , heart failure , medicine , volume overload , cardiology , endocrinology , inflammation , receptor , signal transduction , left ventricular hypertrophy , chemistry , cardiac hypertrophy , blood pressure , biochemistry
Sustained inflammation plays a causal role in the development and progression of LVH and its transition to failure. We hypothesized that pressure overload (PO) amplifies interleukin (IL)‐18 signaling during LVH and failure, and IL‐18 is a potent pro‐hypertrophic cytokine. Results Using a rabbit model, we report that PO by constriction of the descending thoracic aorta induces LVH. Monitoring by echocardiography indicates compensated hypertrophy at 4 weeks (Mass/Volume ratio: 1.7±0.11) and ventricular dilatation indicative of failure at 6 weeks (M/V ratio: 0.7±0.04). We cloned rabbit IL‐18, IL‐18Rα and β, and IL‐18BP full‐length cDNA, and show that PO, while enhancing IL‐18 and IL‐18R expression in hypertrophied and failing hearts, markedly attenuated expression levels of the IL‐18 antagonist IL‐18 binding protein. In vitro, cyclical mechanic stretch (10% cyclic equibiaxial stretch, 1 Hz) induced hypertrophy of cardiomyocytes (CaM) and enhanced IL‐18, IL‐18Rα and ANP‐1 expression. Treatment with rhIL‐18 induced its own expression and that of IL‐18Rα via AP‐1, and CaM hypertrophy via PI3K/Akt/GATA4. Conclusions PO enhances IL‐18 and its receptor expression in hypertrophied and failing hearts. Since IL‐18BP expression is markedly inhibited, our results indicate a positive amplification in IL‐18 inflammatory signaling, and suggest IL‐18 as a potential therapeutic target in LVH and failure.