IKKi deficiency promotes pressure overload-induced cardiac hypertrophy and fibrosis.
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.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
Jia
J
Dai
Di-Fei
DF
Shen
Zhou-Yan
ZY
Bian
Heng
H
Zhou
Hua-Wen
HW
Gan
Jing
J
Zong
Wei
W
Deng
Yuan
Y
Yuan
FangFang
F
Li
Qing-Qing
QQ
Wu
Lu
L
Gao
Rui
R
Zhang
Zhen-Guo
ZG
Ma
Hong-Liang
HL
Li
Qi-Zhu
QZ
Tang
D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D005355:Fibrosis; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D055786:Gene Knockout Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000503:physiopathology; D006439:Hemodynamics; D051550:I-kappa B Kinase / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase; D038362:Glycogen Synthase Kinase 3