No abstract

Purpose. Activation of NLR (nucleotide-binding and leucine-rich repeat immune receptor) family pyrin domain containing 3 (NLRP3) inflammasome mediating interleukin- (IL-) 1β secretion has emerged as an important component of inflammatory processes in atherogenesis. The nuclear receptor Nur77 is highly expressed in human atherosclerotic lesions; however, its functional role in macrophage NLRP3 inflammasome activation has not yet been clarified. Methods, Materials, and Results. Eight-week-old apolipoprotein E (ApoE)−/− and ApoE−/− Nur77−/− mice that were fed a Western diet underwent partial ligation of the left common carotid artery (LCCA) and left renal artery (LRA) to induce atherogenesis. Four weeks later, severe plaque burden associated with increased lipid deposition, reduced smooth muscle cells, macrophage infiltration, and decreased collagen expression was identified in ApoE−/− Nur77−/− mice compared with those in ApoE−/− mice. ApoE−/− Nur77−/− mice showed increased macrophage inflammatory responses in carotid atherosclerotic lesions. In vitro studies demonstrated that oxidized low-density lipoprotein cholesterol (ox-LDL) increased the release of lactate dehydrogenase (LDH) and upregulated the expressions of cleaved caspase-1, cleaved IL-1β and gasdermin D (GSMD) in WT peritoneal macrophages (PMs) in a NLRP3-dependent manner. Nur77−/− PMs exhibited a further increased level of NLRP3 inflammasome-mediated inflammation under ox-LDL treatment compared with WT PMs. Mechanistically, Nur77 could bind to the promoter of NLRP3 and inhibit its transcriptional activity. Conclusions. This study demonstrated that Nur77 deletion promotes atherogenesis by exacerbating NLRP3 inflammasome-mediated inflammation.

Background Abdominal aortic calcification assessed by X-ray is recommended to evaluate vascular calcification in dialysis patients. It has been shown that abdominal aortic calcification score (AACS) is a predictor of adverse outcomes in hemodialysis patients, but evidence regarding its prognostic value in peritoneal dialysis (PD) patients is still insufficient. We aimed to examine the predictive role of AACS for major adverse cardiac and cerebrovascular events (MACCE) and mortality in PD patients.Methods Eligible patients undergoing PD between July 2011 and July 2014 were recruited. AACS was quantified using lateral lumbar radiography at recruitment. Patients were prospectively followed up until death, PD cessation, or to the end of the study (August 31, 2018). Both subdistribution hazards and cause-specific hazards models were used to evaluate the association between AACS and MACCE as well as mortality.Results 292 patients were enrolled, including 160 males (54.8%) with mean age 57.1±15.2 years and median PD duration 28.4 (IQR 12.0, 57.8) months. Among them, 75 (25.7%) patients were comorbid with diabetes, and 94 (32.2%) patients had cardiovascular disease (CVD). The average AACS was 2.0 (0.0, 6.0). Patients were categorized on the tertiles of AACS (Low AACS group, AACS=0, n=125; Medium AACS group, AACS 1-4, n=72; and High AACS group, AACS>4, n=95). AACS was associated with age (OR=1.081, P < 0.001), PD duration (OR=1.012, P=0.003), CVD (OR =1.919, P=0.020) and diabetes (OR=2.554, P=0.002). During the follow-up period of 43.6 (24.6, 50.7) months, there were 65 MACCEs and 84 deaths. Significantly higher cumulative incidences of all-cause mortality (Log-rank = 35.992, P＜0.001; Gray=38.662, P < 0.001) and MACCE (Log-rank=26.146, P＜0.001; Gray=27.810, P < 0.001) were observed in the upper AACS tertile. AACS was an independent predictor of all-cause mortality (HR=2.438, 95% CI 1.246-4.772, P = 0.009; SHR=2.323, 95%CI 1.229-4.389, P=0.009) and MACCE (HR = 3.455, 95% CI 1.734-6.884, P <0.001; SHR=3.063, 95%CI 1.460-6.430, P=0.003) in this study.Conclusions AACS was associated with age, PD duration, CVD and diabetes in PD patients. AACS could predict MACCE and all-cause mortality in this population. It thus might be a safe and feasible method to identify PD patients with adverse outcomes.