1. Overexpression of Hypo-Phosphorylated IκBβ at Ser313 Protects the Heart against Sepsis
- Author
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Zhongshan Wang, Guang-Qing Wang, Li Wang, Zhaofan Xia, Tang Tao, Yingying Liu, and Pengfei Luo
- Subjects
0301 basic medicine ,Male ,Physiology ,medicine.medical_treatment ,Cathepsin L ,lcsh:Medicine ,Gene Expression ,Apoptosis ,Pathology and Laboratory Medicine ,Cardiovascular Physiology ,Biochemistry ,Mathematical and Statistical Techniques ,Serine ,Medicine and Health Sciences ,Myocytes, Cardiac ,Phosphorylation ,Post-Translational Modification ,lcsh:Science ,Energy-Producing Organelles ,Multidisciplinary ,biology ,Cell Death ,Heart ,Mitochondria ,Cytokine ,Cell Processes ,Physical Sciences ,Cytokines ,I-kappa B Proteins ,Anatomy ,Cellular Structures and Organelles ,Statistics (Mathematics) ,Research Article ,Genetically modified mouse ,medicine.medical_specialty ,Transgene ,Autophagic Cell Death ,ATG5 ,Mice, Transgenic ,Bioenergetics ,Research and Analysis Methods ,Sepsis ,03 medical and health sciences ,Signs and Symptoms ,Diagnostic Medicine ,Internal medicine ,medicine ,Autophagy ,Animals ,Statistical Methods ,Analysis of Variance ,Myocardium ,lcsh:R ,Wild type ,Biology and Life Sciences ,Proteins ,Cell Biology ,medicine.disease ,030104 developmental biology ,Endocrinology ,Immunology ,biology.protein ,Cardiovascular Anatomy ,lcsh:Q ,Mathematics - 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.
- Published
- 2016