Translational research : the journal of laboratory and clinical medicine
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The neutrophil plays an important role during abdominal aortic aneurysm (AAA) formation by undergoing histone citrullination with peptidyl arginine deiminase 4 (encoded by Padi4) and releasing neutrophil extracellular traps (NETs). However, the specific role of NETs during AAA formation is elusive. We found the levels of NET components in serum and tissues were found to be significantly associated with the clinical outcome of AAA patients. ⋯ Further studies indicated that the phenotypic switch of SMCs was associated with NETs-regulated enrichment status of H3K4me3 and H3K27me3 at promoters of synthetic and proinflammatory genes in SMCs. Cumulatively, these data suggest that NETs contribute to AAA formation by promoting the synthetic and proinflammatory phenotype of SMCs via inhibiting the Hippo-YAP pathway. A better understanding of the molecular mechanisms that regulate NETs and SMC phenotype is important to provide suitable cellular targets to prevent AAA.
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Cardiac dysfunction has been recognized as a major contributor to mortality in sepsis, which is closely associated with inflammatory reactions. The carboxy terminus of Hsc70-interacting protein (CHIP), a U-box E3 ubiquitin ligase, defends against cardiac injury caused by other factors, but its role in sepsis-induced cardiac dysfunction has yet to be determined. The present study was designed to investigate the effects of CHIP on cardiac dysfunction caused by sepsis and the molecular mechanisms underlying these processes. ⋯ Furthermore, we found that the therapeutic effect of compound YL-109 on cardiac dysfunction in septic mice was due to the upregulation of myocardial CHIP expression. These findings demonstrated that sepsis-initiated the activation of c-Jun suppressed CHIP transcription. CHIP directly promoted ubiquitin-mediated degradation of KPNA2, which reduced the production of proinflammatory cytokines by inhibiting the translocation of NF-κB from the cytoplasm into the nucleus in myocardium, thereby attenuating sepsis-induced cardiac dysfunction.
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Age is the most important risk factor for cardiovascular disease and appears to be more than a marker of cumulative exposure to other risk factors such as dyslipidemia and hypertension. With aging, genetic mutations occur that are not present in our germline DNA, observed as somatic mosaicism. Hematopoietic stem cells have an increased chance of developing mosaicism because they are highly proliferative, and mutations with survival benefits can establish clonal populations. ⋯ The subset of clonal hematopoiesis in which a driver mutation with variant allele frequency of at least 2% occurs in a gene implicated in hematologic malignancies but in the absence of known hematologic malignancy or other clonal disorder is termed clonal hematopoiesis of indeterminate potential (CHIP). Large-scale exome-sequencing projects have recently enabled the study of CHIP frequency, gene-specific analyses, and longitudinal clinical consequences of CHIP, including an observed increased risk for cardiovascular disease. Animal models provide insight into the mechanisms by which CHIP increases cardiovascular disease risk, and combined animal, clinical, and epidemiological data suggest therapeutic implications for CHIP in cardiovascular disease prevention.
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While natriuretic peptides (NPs) are primarily known for their renal and cardiovascular actions, NPs stimulate lipolysis in adipocytes and induce a thermogenic program in white adipose tissue (WAT) that resembles brown fat. The biologic effects of NPs are negatively regulated by the NP clearance receptor (NPRC), which binds and degrades NPs. Knockout (KO) of NPRC protects against diet induced obesity and improves insulin sensitivity in obese mice. ⋯ These beneficial effects were accompanied by a decrease in infiltrating macrophages in adipose tissue, and reduced expression of inflammatory markers in both serum and WAT. These data suggest that inhibiting NP clearance may be an effective pharmacologic approach to promote weight loss and enhance insulin sensitivity in type 2 diabetes. Optimizing the therapeutic approach may lead to useful therapies for obesity and type 2 diabetes.
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Cell inflammation and death are closely linked processes contributing to endothelial dysfunction, which plays a critical role in atherogenesis. Activation of the NLRP3 inflammasome causes pyroptosis, the Gasdermin D (GSDMD)-mediated inflammatory cell death. The non-canonical NF-κB pathway has been implicated in inflammation; however, its role in NLRP3 inflammasome-mediated endothelial dysfunction has not been investigated. ⋯ Consistent with the observations in cultured endothelium, endothelial-specific deficiency of NIK or IRF-1 attenuated atherosclerosis in high-fat diet-fed Apoe-null mice. These data demonstrate that the non-canonical NF-κB pathway contributes to NLRP3 inflammasome-mediated endothelial pyroptosis and the development of atherosclerosis through GSDMD activation in a manner dependent on IRF-1. Further investigation may facilitate the identification of specific therapeutic targets for atherosclerotic heart diseases.