title: Overexpression of Hypo-Phosphorylated IκBβ at Ser313 Protects the Heart against Sepsis.
abstract: IκBβis an inhibitor of nuclear factor kappa B(NF-κB) and participates in the cardiac response to sepsis. However, the role of the hypo-phosphorylated form of IκBβ at Ser313, which can be detected during sepsis, is unknown. Here, we examined the effects of IκBβ with a mutation at Ser313→Ala313 on cardiac damage induced by sepsis. Transgenic (Tg) mice were generated to overexpress IκBβ, in which Ser-313 is replaced with alanine ubiquitously, in order to mimic the hypo-phosphorylated form of IκBβ. Survival analysis showed that Tg mice exhibited decreased inflammatory cytokine levels and decreased rates of mortality in comparison to wild type (WT) mice, after sepsis in a cecal-ligation and puncture model (CLP). Compared to WT septic mice, sepsis in Tg mice resulted in improved cardiac functions, lower levels of troponin I and decreased rates of cardiomyocyte apoptosis, compared to WT mice. The increased formation of autophagicvacuoles detected with electron microscopy demonstrated the enhancement of cardiac autophagy. This phenomenon was further confirmed by the differential expression of genes related to autophagy, such as LC3, Atg5, Beclin-1, and p62. The increased expression of Cathepsin L(Ctsl), a specific marker for mitochondrial stress response, may be associated with the beneficial effects of the hypo-phosphorylated form of IκBβ. Our observations suggest that the hypo-phosphorylated form of IκBβ at Ser313 is beneficial to the heart in sepsis through inhibition of apoptosisand enhancement of autophagy in mutated IκBβ transgenic mice.
authors: Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Guang-Qing
authors: GQ
authors: Wang
authors: Department of Surgery, 91528 Hospital of PLA, Shanghai, China.
authors: Tao
authors: T
authors: Tang
authors: Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Zhong-Shan
authors: ZS
authors: Wang
authors: Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Ying-Ying
authors: YY
authors: Liu
authors: Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Li
authors: L
authors: Wang
authors: Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Peng-Fei
authors: PF
authors: Luo
authors: Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Zhao-Fan
authors: ZF
authors: Xia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000235:genetics; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology*; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D018805:Sepsis / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology*; D012694:Serine / Q000378:metabolism
chemical_list: D016207:Cytokines; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D012694:Serine; D056668:Cathepsin L; C534278:Ctsl protein, mouse