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, 23 (1), 55

MicroRNA Profiling of Diabetic Atherosclerosis in a Rat Model

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MicroRNA Profiling of Diabetic Atherosclerosis in a Rat Model

Yuejin Li et al. Eur J Med Res.

Abstract

Objective: The incidence of diabetic atherosclerosis (DA) is increasing worldwide. The study aim was to identify differentially expressed microRNAs (DE-miRs) potentially associated with the initiation and/or progression of DA, thereby yielding new insights into this disease.

Methods: Matched iliac artery tissue samples were isolated from 6 male rats with or without DA. The Affymetrix GeneChip microRNA 4.0 Array was used to detect miRs. Differential expression between atherosclerotic group and non-atherosclerotic group samples was analyzed using the Gene-Cloud of Biotechnology Information platform. Targetscan and miRanda were then used to predict targets of DE-miRs. Functions and pathways were identified for significantly enriched candidate target genes and a DE-miR functional regulatory network was assembled to identify DA-associated core target genes.

Results: A total of nine DE-miRs (rno-miR-206-3p, rno-miR-133a-5p, rno-miR-133b-3p, rno-miR-133a-3p, rno-miR-325-5p, rno-miR-675-3p, rno-miR-411-5p, rno-miR-329-3p, and rno-miR-126a-3p) were identified, all of which were up-regulated and together predicted to target 3349 genes. The target genes were enriched in known functions and pathways related to lipid and glucose metabolism. The functional regulatory network indicated a modulatory pattern of these metabolic functions with DE-miRs. The miR-gene network suggested arpp19 and MDM4 as possible DA-related core target genes.

Conclusion: The present study identified DE-miRs and miRNA-gene networks enriched for lipid and glucose metabolic functions and pathways, and arpp19 and MDM4 as potential DA-related core target genes, suggesting DE-miRs and/or arpp19 and MDM4 could act as potential diagnostic markers or therapeutic targets for DA.

Keywords: Diabetic atherosclerosis; Differentially expressed miRNA; miRNA-gene regulatory network.

Figures

Fig. 1
Fig. 1
A Body weight monitoring of AG and NAG diabetic rats. Rats in the AG group weighed more before week 8, after which time AG rat weight decreased to a statistically significant lower level compared with NAG rats. B Random blood glucose levels in AG and NAG diabetic rats. After week 7 the mean blood glucose of NAG rats remained significantly higher than that of AG rats. C Doppler ultrasound examination of lesion morphology in iliac artery transverse sections in DA and non-DA rats (NAG: a, b, c; AG: d, e, f). Yellow arrows indicate iliac vascular walls. D Aortic, renal, and iliac arteries. Green arrow: aorta. Blue arrow: renal artery. Yellow arrows indicate the iliac artery where samples were collected. Red arrow indicates the iliac artery transverse section analyzed by Doppler ultrasound. *P < 0.05, **P < 0.01
Fig. 2
Fig. 2
a Fold change in expression of 10 DE-miRs. b Heatmap of the 10 DE-miRs. The clustering feature trees on the left and above the heat map show stepwise miRNA connections and sample clustering, respectively. MiRNAs shown in red had higher expression levels compared with those in green. **P < 0.01
Fig. 3
Fig. 3
qRT-PCR analysis of relative miRNA expression. N = 6
Fig. 4
Fig. 4
Comparative qRT-PCR and microarray gene chip analysis. N = 6
Fig. 5
Fig. 5
a Network of DE-miRs and their enriched functions. The enriched metabolic functions are labeled. b DE-miR modulatory pattern of enriched metabolic functions. The enriched glucose and lipid metabolism functions regulated by DE-miRs in which “insulin receptor signaling pathway”, “response to glucose stimulus”, “cellular response to insulin stimulus”, “positive regulation of insulin secretion” and “negative regulation of insulin secretion” were targeted by the most miRNAs, suggesting important roles in DA regulation. rno-miR-329-3p, 133a-5p, 325-5p, 133a-3p, and 133b-3p were predicted to modulate the majority of these metabolic functions
Fig. 6
Fig. 6
a Network of DE-miRs and their target genes. The 15 core target genes regulated by the most DE-miRs (≥ 4) are labeled. b MiRNA modulatory pattern of arpp19 and MDM4 and their possible functions in the initiation and development of DA. rno-miR-133a-3p, 133a-5p, and 133b-3p regulated both genes
Fig. 7
Fig. 7
a The transcript levels of arpp19 and MDM4 in AG and NAG diabetic rats. b The protein levels of arpp19 and MDM4 in AG and NAG diabetic rats. N = 6

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