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I?B Kinase Inhibitor Attenuates Sepsis-Induced Cardiac Dysfunction in CKD.

ABSTRACT: Patients with CKD requiring dialysis have a higher risk of sepsis and a 100-fold higher mortality rate than the general population with sepsis. The severity of cardiac dysfunction predicts mortality in patients with sepsis. Here, we investigated the effect of preexisting CKD on cardiac function in mice with sepsis and whether inhibition of I?B kinase (IKK) reduces the cardiac dysfunction in CKD sepsis. Male C57BL/6 mice underwent 5/6 nephrectomy, and 8 weeks later, they were subjected to LPS (2 mg/kg) or sepsis by cecal ligation and puncture (CLP). Compared with sham operation, nephrectomy resulted in significant increases in urea and creatinine levels, a small (P<0.05) reduction in ejection fraction (echocardiography), and increases in the cardiac levels of phosphorylated I?B?, Akt, and extracellular signal-regulated kinase 1/2; nuclear translocation of the NF-?B subunit p65; and inducible nitric oxide synthase (iNOS) expression. When subjected to LPS or CLP, compared with sham-operated controls, CKD mice exhibited exacerbation of cardiac dysfunction and lung inflammation, greater increases in levels of plasma cytokines (TNF-?, IL-1?, IL-6, and IL-10), and greater increases in the cardiac levels of phosphorylated IKK?/? and I?B?, nuclear translocation of p65, and iNOS expression. Treatment of CKD mice with an IKK inhibitor (IKK 16; 1 mg/kg) 1 hour after CLP or LPS administration attenuated these effects. Thus, preexisting CKD aggravates the cardiac dysfunction caused by sepsis or endotoxemia in mice; this effect may be caused by increased cardiac NF-?B activation and iNOS expression.

SUBMITTER: Chen J

PROVIDER: S-EPMC5198262 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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IκB Kinase Inhibitor Attenuates Sepsis-Induced Cardiac Dysfunction in CKD.

Chen Jianmin J Kieswich Julius E JE Chiazza Fausto F Moyes Amie J AJ Gobbetti Thomas T Purvis Gareth S D GS Salvatori Daniela C F DC Patel Nimesh S A NS Perretti Mauro M Hobbs Adrian J AJ Collino Massimo M Yaqoob Muhammad M MM Thiemermann Christoph C

Journal of the American Society of Nephrology : JASN 20160506 1

Patients with CKD requiring dialysis have a higher risk of sepsis and a 100-fold higher mortality rate than the general population with sepsis. The severity of cardiac dysfunction predicts mortality in patients with sepsis. Here, we investigated the effect of preexisting CKD on cardiac function in mice with sepsis and whether inhibition of IκB kinase (IKK) reduces the cardiac dysfunction in CKD sepsis. Male C57BL/6 mice underwent 5/6 nephrectomy, and 8 weeks later, they were subjected to LPS (2 ...[more]

PMID: 27153924

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Project description:The development of cardiac dysfunction caused by microbial infection predicts high mortality in sepsis patients. Specialized pro-resolving mediators (SPMs) mediate resolution of inflammation in many inflammatory diseases, and are differentially expressed in plasma of sepsis patients. Here, we investigated whether the levels of SPMs are altered in the murine septic heart following polymicrobial sepsis-induced cardiac dysfunction. Ten weeks-old male C57BL/6 mice were subjected to polymicrobial sepsis induced by cecal ligation and puncture (CLP), which is a clinically relevant sepsis model receiving analgesics, antibiotics, and fluid resuscitation. CLP caused a significant systolic dysfunction assessed by echocardiography. The hearts were subjected to LC-MS/MS based lipid mediator profiling. Many SPMs were significantly reduced in septic hearts, among which RvE1 had a ~93-fold reduction. Treatment of CLP mice with synthetic RvE1 (1 μg/mouse i.v.) at 1 h after CLP increased peritoneal macrophages number, particularly MHC II- macrophages. RvE1 reduced pro-inflammatory gene expression (interleukin-1β, interleukin-6, and CCL2) in lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDMs) in vitro. RvE1 attenuated cardiac dysfunction in septic mice and increased cardiac phosphorylated Akt; decreased cardiac phosphorylated IκB kinase α/β, nuclear translocation of the NF-κB subunit p65, extracellular signal-regulated kinase 1/2, and c-Jun amino-terminal kinases 1/2. Most notably, RvE1 treatment reduced peritoneal bacterial load and promoted phagocytosis activity of BMDMs. In conclusion, cardiac SPMs, particularly RvE1, are substantially reduced in mice with polymicrobial sepsis. Delayed therapeutic administration of RvE1 to mice with polymicrobial sepsis attenuates the cardiac dysfunction through modulating immuno-inflammatory responses. In addition to the above effects, the ability to enhance bacterial clearance makes RvE1 an ideal therapeutic to reduce the sequalae of polymicrobial sepsis.

Project description:Aims: Cardiac dysfunction can be a fatal complication during severe sepsis. The migration of neutrophils is significantly impaired during severe sepsis. We sought to determine the role of trimetazidine (TMZ) in regulation of neutrophil migration to the heart in a mouse model of sepsis and endotoxemia, and to identify the mechanism whereby TMZ confers a survival advantage. Methods and Results: C57/BL6 mice were (1) injected with LPS followed by 24-h TMZ administration, or (2) treated with TMZ (20 mg/kg/day) for 1 week post cecal ligation and puncture (CLP) operation. Echocardiography and Millar system detection showed that TMZ alleviated cardiac dysfunction and histological staining showed the failure of neutrophils migration to heart in both LPS- and CLP-induced mice. Bone marrow transplantation revealed that TMZ-pretreated bone marrow cells improved LPS- and CLP-induced myocardial dysfunction and enhanced neutrophil recruitment in heart. In CXCL2-mediated chemotaxis assays, TMZ increased neutrophils migration via AMPK/Nrf2-dependent up-regulation of CXCR2 and inhibition of GRK2. Furthermore, using luciferase reporter gene and chromatin immunoprecipitation assays, we found that TMZ promoted the binding of the Nrf2 and CXCR2 promoter regions directly. Application of CXCR2 inhibitor completely reversed the protective effects of TMZ in vivo. Co-culture of neutrophils and cardiomyocytes further validated that TMZ decreased LPS-induced cardiomyocyte pyroptosis by targeting neutrophils. Conclusion: Our findings suggested TMZ as a potential therapeutic agent for septic or endotoxemia associated cardiac dysfunction in mice. STUDY HIGHLIGHTS What is the current knowledge on the topic? Migration of neutrophils is significantly impaired during severe sepsis, but the underlying mechanisms remain unknown. What question did this study address? The effects of TMZ on cardiac dysfunction via neutrophils migration. What this study adds to our knowledge TMZ attenuated LPS-induced cardiomyocyte pyroptosis and cardiac dysfunction by promoting neutrophils recruitment to the heart tissues via CXCR2. How this might change clinical pharmacology or translational science Our findings suggested TMZ as a potential therapeutic agent for septic cardiac dysfunction.

Dataset Information

I?B Kinase Inhibitor Attenuates Sepsis-Induced Cardiac Dysfunction in CKD.

Publications

IκB Kinase Inhibitor Attenuates Sepsis-Induced Cardiac Dysfunction in CKD.

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