Effect of Sirt7 depletion on gene expression of primary murine vascular smooth muscle cells isolated from c57bl/6
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE247550 | GEO | 2023/12/01
REPOSITORIES: GEO
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Project description:Vascular calcification, the ectopic deposition of calcium in blood vessels, develops in association with various metabolic diseases and atherosclerosis. Because it often causes stiffness and remodeling of the blood vessels, vascular calcification increases morbidity and mortality. Both miRNA and mRNA microarrays (Series GSE74755) were performed with rat VSMCs and reciprocally regulated pairs of miRNA and mRNA were selected after bioinformatic analysis.
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Project description:Aims/hypothesis. Ectopic calcification is a typical feature of diabetic vascular disease and resembles an accelerated aging phenotype. We previously found an excess of myeloid calcifying cells (MCCs) in diabetic patients. We herein examined molecular and cellular pathways linking atherosclerotic calcification with calcification by myeloid cells in the diabetic milieu. Methods. We first examined the associations among coronary calcification, MCC levels, and mononuclear cell gene expression in a cross-sectional study of 87 type 2 diabetic patients undergoing elective coronary angiography. Then, we undertook in vitro studies on mesenchymal stem cells (MSCs) and on the THP-1 myeloid cells line to verify the causal relationships of the observed associations. Results. Coronary calcification was associated with 2.8-times higher MCC levels (p=0.037) and 50% elevated expression of the osteogenic gene RUNX2 in mononuclear cells, whereas expression of Sirtuin-7 (SIRT7) was inversely correlated with calcification. In standard differentiation assays of MSCs, SIRT7 knockdown activated the osteogenic program and worsened calcification, especially in the presence of high (20 mM) glucose. In the monocytic cell line THP-1, SIRT7 downregulation drove a pro-calcific phenotype, whereas SIRT7 overexpression prevented high-glucose induced calcification. Through the JAK/STAT pathway, high glucose induced miR-125b-5p, which in turn targeted SIRT7 in myeloid cells and was directly associated with coronary calcification. Conclusions/interpretation. We describe a new pathway elicited by high glucose trough the JAK/STAT cascade, involving regulation of SIRT7 by mir-125b-5p driving calcification by myeloid cells. This pathway is associated with coronary calcification in diabetic patients and may be a target to tackle diabetic vascular disease.
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Project description:Medial arterial calcification is a chronic systemic vascular disorder distinct from atherosclerosis and is commonly observed in patients with chronic kidney disease (CKD), diabetes mellitus, and aging individuals. We previously showed that orphan nuclear receptor NR4A3 is a key regulator in the progression of apolipoprotein (apo) A-IV-induced atherosclerosis; however, little is known about its role in vascular calcification. NR4A3 expression was upregulated in calcified aortic tissues from CKD mice or 1,25(OH)2VitD3 overload-induced mice, and in human calcified aorta. NR4A3 deficiency preserved VSMCs contractile phenotype, inhibited the expression of osteoblast differentiation-related genes, and reduced calcium deposition in the vasculature.
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Project description:Medial arterial calcification is a chronic systemic vascular disorder distinct from atherosclerosis and is commonly observed in patients with chronic kidney disease (CKD), diabetes mellitus, and aging individuals. We previously showed that orphan nuclear receptor NR4A3 is a key regulator in the progression of apolipoprotein (apo) A-IV-induced atherosclerosis; however, little is known about its role in vascular calcification. NR4A3 expression was upregulated in calcified aortic tissues from CKD mice or 1,25(OH)2VitD3 overload-induced mice, and in human calcified aorta. NR4A3 deficiency preserved VSMCs contractile phenotype, inhibited the expression of osteoblast differentiation-related genes, and reduced calcium deposition in the vasculature.
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