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Regulation of succinate signaling and immunometabolism in diabetes-associated atherosclerosis by miR-369-3p

ABSTRACT: Atherosclerosis is accelerated under diabetic conditions in part due to altered macrophage metabolism and function. Identifying critical factors to restore metabolic alterations and promote resolution of inflammation remains an unmet goal. MicroRNAs (miRs) orchestrate multiple signaling events in macrophages and regulate inflammation, yet their therapeutic potential in diabetes-associated atherosclerosis remains poorly understood. miRNA profiling of aortic intimal lesions from Ldlr-/- mice on a high-fat sucrose containing (HFSC) diet for 12 weeks revealed low expression of miR-369-3p. miR-369-3p was also reduced in peripheral blood mononuclear cells (PBMCs) from diabetic patients with coronary artery disease. Cell-type expression profiling showed miR-369-3p enrichment in aortic macrophages. Treatment with oxLDL reduced miR-369-3p expression in-stimulation mouse bone marrow-derived macrophages (BMDMs) downregulated miR-369-3p. Overexpression of miR-369-3p restored the oxLDL-mediated decrease of OXPHOS in BMDMs. Mechanistically, we found that miR-369-3p targeted the succinate receptor (GPR91) to alleviate the oxLDL-induced activation of inflammasome signaling pathways. Therapeutic administration of miR-369-3p in HFSC-fed Ldlr-/- mice reduced GPR91 expression in lesional macrophages and the diabetes-mediated accelerated atherosclerosis, evident by a decrease in plaque size and in the accumulation of pro-inflammatory Ly6Chi macrophages. RNA-seq analyses showed more pro-resolving pathways in plaque macrophages from miR-369-3p treated mice, consistent with an increase in macrophage efferocytosis in lesions. These findings establish a therapeutic role for miR-369-3p in halting diabetes-associated atherosclerosis by regulating GPR91 and macrophage succinate metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE244760 | GEO | 2024/12/04

REPOSITORIES: GEO

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Project description:Adipose tissue inflammation and atherosclerosis are the main mechanisms behind type 2 diabetes and cardiovascular disease respectively, the major risks associated with the metabolic syndrome. Studies considering more than single factors behind the complexity of the metabolic syndrome are valuable to achieve a better and wider understanding of the metabolic syndrome. In this study common dysregulated pathways between adipose tissue inflammation and atherosclerosis were identified using two different bioinformatic tools to perform pathway analysis. First, we run a gene set enrichment analysis utilizing with data from two microarray experiments done with gonadal white adipose tissue and atherosclerotic aorta. Once the common dysregulated pathways between both tissues were identify, the inflammatory response and the oxidative phosphorylation pathways from the Hallmark geneset were selected to conduct a deeper checkup at the single gene level of these pathways. Second, we carried out a pathway analysis validation with the Pantherâ¢ software combining the microarray data with a published type 2 diabetes mellitus metanalysis and cardiovascular disease metanalysis which included human data. In conclusion, this study provides worthwhile data pointing out and describing several dysregulated and common pathways in adipose tissue inflammation and atherosclerotic aorta with a potential implication in the pathogenesis of type 2 diabetes and atherosclerosis. LDLR-/- on a C57BL/6J background, purchased from Charles River Laboratories (Sulzfeld, Germany) were used. At 9 weeks of age the LDLR-/- were placed for up to 20 weeks on sucrose-enriched high-fat diet (HFSC) (with 17.5 kcal% from sucrose; (D09071704, Research Diets Inc.). Their respective controls were kept on normal chow diet (NC) for up to 20 weeks. After sacrificing the gonadal white adipose tissue (GWAT) from LDLR-/- animals on NC (Samples 22-27) or HFSC (Samples 28-33) was collected as well as the whole aortae from LDLR-/- animals on NC (Samples 13-15) or HFSC (Samples16-18). The collected tissues were immediately snap frozen in liquid nitrogen. RNA was isolated for gene expression microarray analyses at the exon level (GeneChip Mouse Exon 2.0 ST Array, Affymetrix, Santa Clara, CA, USA). To isolate RNA, the frozen tissue samples were homogenized in TRIzolÂ® reagent (Invitrogen/Life Technologies, Carlsbad, CA, USA) and processed based on manufacturerâs instructions. Total RNA (1Î¼g) was then used for GeneChip analysis, individual samples were used in GWAT preparation and three samples were pooled and used for aorta preparations. Terminal-labeled cDNA, hybridization to genome-wide Mouse Gene 2.0 ST Gene Chips and scanning of the arrays were carried out according to the manufactureâs indications (Affymetrix).Output primary row data was analyzed with Expression Console software (Affymetrix).

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Regulation of succinate signaling and immunometabolism in diabetes-associated atherosclerosis by miR-369-3p

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