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Effect of TUDCA on the artery which suffered from the atherosclerosis in ApoE-/- mice

ABSTRACT: Cholesterol efflux capacity dysfunction in macrophages is thought to be important in atherosclerosis. However, the molecular mechanism underlying this dysfunction remains unclear. Our previous analysis found that the increase of endoplasmic reticulum stress in macrophages during atherosclerotic plaque formation. Here we extended our analysis to ApoE-/- mice fed a high fat diet, some of which were treated with tauroursodeoxycholic acid (TUDCA) and collected the arteries of mice among these three groups (NFD, HFD and HFD+TUDCA) to perform the Bulk-RNA sequencing. There was significantly high expression of matrix metalloproteinase family (MMP9, MMP25, MMP8, MMP12, MMP13 and MMP3), CD68, inflammasome (IL1b, IL18bp, ifi44, ifi204 and Nlrp3), ER stress (Hspa5) and cholesterol transporters (ABCA1 and ABCG1) in the HFD group compared with the NFD group, however, TUDCA rescued the high expression of the above DEGs to different degrees. As shown by the expression levels of ifi204, Nlrp3, Il1b, and Il18, inflammasome activation was evident in the arteries of the HFD group compared to the NFD group. The ER stress inhibitor TUDCA not only decreased expression of the ER stress-related gene Hspa5 but also down-regulated inflammasome activation (as seen with the expression levels of ifi204, ifi44, NLRP3 and IL1b) in the artery of TUDCA treated mice compared with mice without drugs.

ORGANISM(S): Mus musculus

PROVIDER: GSE260610 | GEO | 2024/03/05

REPOSITORIES: GEO

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Project description:Inflammasome, activated by pathogen-derived and host-derived danger signals, constitutes a multimolecular signaling complex that serves as a platform for caspase-1 (CASP1) activation and interleukin-1beta (IL1B) maturation. The activation of NLRP3 inflammasome requires two-step signals. The first “priming” signal (Signal 1) enhances gene expression of inflammasome components. The second “activation” signal (Signal 2) promotes the assembly of inflammasome components. Deregulated activation of NLRP3 inflammasome contributes to the pathological processes of Alzheimer’s disease (AD) and multiple sclerosis (MS). However, at present, the precise mechanism regulating NLRP3 inflammasome activation and deactivation remains largely unknown. By genome-wide gene expression profiling, we studied the molecular network of NLRP3 inflammasome activation-responsive genes in a human monocyte cell line THP-1 sequentially given two-step signals. We identified the set of 83 NLRP3 inflammasome activation-responsive genes. Among them, we found the NR4A nuclear receptor family NR4A1, NR4A2, and NR4A3, the EGR family EGR1, EGR2, and EGR3, the IkappaB family NFKBIZ, NFKBID, and NFKBIA as a key group of the genes that possibly constitute a negative feedback loop for shutting down inflammation following NLRP3 inflammasome activation. By molecular network analysis, we identified a complex network of NLRP3 inflammasome activation-responsive genes involved in cellular development and death, and immune and inflammatory responses, where transcription factors AP-1, NR4A, and EGR serve as a hub. Thus, NLRP3 inflammasome activation-responsive genes constitute the molecular network composed of a set of negative feedback regulators for prompt resolution of inflammation. To load the Signal 1 (S1), THP-1 cells were incubated for 3 hours in the culture medium with or without inclusion of 0.2 microgram/ml lipopolysaccharide (LPS). To load the Signal 2 (S2), they were incubated further for 2 hours in the culture medium with inclusion of 10 microM nigericin sodium salt dissolved in ethanol or the equal v/v% concentration of ethanol (vehicle), followed by processing for microarray analysis on Human Gene 1.0 ST Array (Affymetrix).

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Effect of TUDCA on the artery which suffered from the atherosclerosis in ApoE-/- mice

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