Translational research : the journal of laboratory and clinical medicine
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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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Takayasu arteritis (TAK) is a chronic large vessel disease characterized by aortic fibrotic thickening, which was mainly mediated by activation of aorta adventitial fibroblasts (AAFs). Our previous genetic study demonstrated that TAK-associated locus IL6 rs2069837 regulated glycoprotein non-metastatic melanoma protein B (GPNMB) expression. Thus, this study aimed to investigate the pathogenic role of GPNMB in TAK. ⋯ Furthermore, we showed that leflunomide treatment inhibited GPNMB-mediated fibrosis in AAFs, as well as GPNMB expression in macrophages, which were also partially validated in leflunomide-treated patients. Taken together, these data indicated that macrophage-derived GPNMB promotes AAFs ECM expression via the integrin αVβ1 receptor and Akt/Erk signaling pathway and leflunomide might play an anti-fibrotic role in TAK by interfering with the macrophage-derived GPNMB/AAFs axis. This study provides evidence that targeting GPNMB is a potential therapeutic strategy for treating vascular fibrosis in TAK.
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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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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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Dendritic cells (DCs) are key regulators of the adaptive immune response. Tolerogenic dendritic cells play a crucial role in inducing and maintaining immune tolerance in autoimmune diseases such as type 1 diabetes in humans as well as in the NOD mouse model. We previously reported that bone marrow-derived DCs (BM. ⋯ Furthermore, analysis of C/EBPβ-/- GM/DCs demonstrated that C/EBPβ is required for IL-23 production. Of physiological relevance, the level of protection from diabetes following transfusion of GM/DCs into young NOD mice was significantly reduced when NOD mice were transfused with GM/DCs pretreated with a PI3K inhibitor. Our data suggest that PI3K/C/EBPβ signaling is important in controlling tolerogenic function of GM/DCs by limiting their Th17-promoting cytokines.