Abstract 13093: The Inducible Nuclear Protein IκBζ Plays a Pivotal Role in the Transition From Adaptive to Maladaptive Cardiac Hypertrophy During Pressure Overload
Background: Inflammation has been implicated in the pathophysiology of both adaptive and maladaptive cardiac hypertrophy in response to pressure overload. However, it remains unclear how chronic inflammation contributes to the transition from adaptive to maladaptive cardiac hypertrophy. Interleukin-1β (IL-1β) has been shown to induce Akt phosphorylation, which plays an important role in cardiac adaptive response to pressure overload, whereas chronic IL-6 signaling has been reported to inhibit Akt phosphorylation through induction of suppressor of cytokine signaling (SOCS) 3. IκBζ, encoded by the NFKBIZ gene, is an inducible nuclear protein which regulates the transition from IL-1β expression to IL-6 expression in the NF-κB system. This study was performed to clarify the role of IκBζ in pressure overload-induced cardiac hypertrophy.
Methods and Results: Pressure overload was induced in Nfkbiz+/+ and Nfkbiz+/- mice by transverse aortic constriction (TAC). In Nfkbiz+/+ mice, TAC-operated hearts showed adaptive cardiac hypertrophy until 2 weeks after the operation, whereas at 4 weeks after TAC, impaired systolic function with left ventricular dilatation was observed (n=10). TAC-operated Nfkbiz+/- hearts showed similar adaptive cardiac hypertrophy to TAC-operated Nfkbiz+/+ hearts until 2 weeks after the operation (n=10). However, at 4 weeks after TAC, Nfkbiz+/- hearts showed preserved systolic function with attenuated LV dilatation compared with Nfkbiz+/+ hearts. Real time PCR revealed that IL-1β mRNA expression levels were higher in Nfkbiz+/- hearts than in Nfkbiz+/+ hearts at 4 weeks after TAC (n=5), whereas mRNA expression levels of IL-6 and SOCS3 were higher in Nfkbiz+/+ hearts that in Nfkbiz+/- hearts. Western blot analysis demonstrated that Akt phosphorylation levels were higher in Nfkbiz+/- hearts that in Nfkbiz+/+ hearts at 4 weeks after TAC.
Conclusions: Our results suggest that IκBζ plays a pivotal role in the transition from adaptive to maladaptive cardiac hypertrophy during pressure overload, possibly in part, through the regulation of proinflammatory cytokine expression pattern in the heart tissue, which may regulate Akt phosphorylation levels. Thus, IκBζ may be a novel therapeutic target for treating heart failure.
Author Disclosures: Y. Higashikuni: None. D. Fukuda: None. M. Sata: None. I. Komuro: None.
- © 2014 by American Heart Association, Inc.