Abstract
The inducible IκB kinase (IKKi/IKKε) is a recently described serine-threonine IKK-related kinase. Previous studies have reported the role of IKKi in infectious diseases and cancer. However, its role in the cardiac response to pressure overload remains elusive. In this study, we investigated the effects of IKKi deficiency on the development of pathological cardiac hypertrophy using in vitro and in vivo models. First, we developed mouse models of pressure overload cardiac hypertrophy induced by pressure overload using aortic banding (AB). Four weeks after AB, cardiac function was then assessed through echocardiographic and hemodynamic measurements. Western blotting, real-time PCR and histological analyses were used to assess the pathological and molecular mechanisms. We observed that IKKi-deficient mice showed significantly enhanced cardiac hypertrophy, cardiac dysfunction, apoptosis and fibrosis compared with WT mice. Furthermore, we recently revealed that the IKKi-deficient mice spontaneously develop cardiac hypertrophy. Moreover, in vivo experiments showed that IKKi deficiency-induced cardiac hypertrophy was associated with the activation of the AKT and NF-κB signaling pathway in response to AB. In cultured cells, IKKi overexpression suppressed the activation of this pathway. In conclusion, we demonstrate that IKKi deficiency exacerbates cardiac hypertrophy by regulating the AKT and NF-κB signaling pathway.
Highlights
Heart failure (HF) is a debilitating disease with a high prevalence, morbidity and mortality [1,2,3,4,5]
We found that IKKi protein and mRNA levels were slightly increased at 1 week but significantly up-regulated at 4 and 8 weeks after aortic banding (AB) (Figure 1)
It was documented that the heart weight (HW), HW/body weight (BW), HW/tibial length (TL), LVEDD, and LVESD were significantly increased and the fractional shortening (FS) was decreased compared with the WT mice (Table 1), which agrees with our hypothesis that the loss of IKKi leads to spontaneous cardiac hypertrophy and dysfunction
Summary
Heart failure (HF) is a debilitating disease with a high prevalence, morbidity and mortality [1,2,3,4,5]. Recent studies have shown that signaling pathways and their associated molecules play complex and pivotal roles in the development of cardiac hypertrophy,including mitogen activated protein kinases (MAPKs), phosphatidylinositol 3-kinase(PI3K)/AKT and calcineurin/nuclear factor of activated T cells (NFAT) [10]. The identification of signals and pathways involved in pathological hypertrophy would open the door for the development of future therapeutic interventions for heart failure. Nuclear factor-kB (NF-kB) plays a critical role in the immune response and influences gene expression events that affect cell survival, apoptosis, differentiation, proliferation, cancer progression and development [11,12]. The NF-kB family of transcription factors includes five members, p50, p52, p65 (RelA), c-Rel, and RelB These members share an N-terminal Rel homology domain (RHD),which is responsible for DNA binding and homo- and heterodimerization [11,12]. The freed NF-kB translocates to the nucleus, where it binds to and activates the promoters of the NFkB responsive genes [11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
