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 It remains controversial whether contrast-associated acute kidney injury (CA-AKI) is associated with long-term major adverse kidney events (MAKE) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Methods By the Acute Kidney Injury Network (AKIN) criteria, CA-AKI was defined as an increase in serum creatinine ≥ 0.3 mg/dL or 50% from baseline within 48 h after PCI; or an increase in serum creatinine ≥ 0.5 mg/dL or 25% within 72 h by the contrast-induced nephropathy (CIN) criteria. The primary endpoint was 1-year MAKE, defined as a composite of all-cause mortality and persistent renal dysfunction. Results A total of 402 patients were finally included in this study. The primary endpoint occurred in 29 (7.2%) patients. There was a significant association between CA-AKI and 1-year MAKE assessed by both the AKIN (hazard ratios [HR]: 11.58, 95% confidence interval [CI]: 4.29–31.24, p = 0.000) and CIN (HR: 6.45, 95% CI: 2.56–16.25, p = 0.000) definitions. However, the AKIN definition (HR: 4.95, 95% CI: 1.17–21.02, p = 0.030) was more reliable in the prediction of persistent renal dysfunction than CIN definition (HR: 4.08, 95% CI: 0.99–16.87, p = 0.052). Additionally, the area under receiver operating characteristic curve was larger for predicting 1-year MAKE with the AKIN definition than CIN definition (0.742 vs. 0.727). Conclusions In patients with STEMI undergoing primary PCI, CA-AKI was significantly associated with 1-year MAKE. Moreover, the AKIN definition might be more reliable in the prediction of long-term prognosis.
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