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. 2022 Dec:58:102531.
doi: 10.1016/j.redox.2022.102531. Epub 2022 Nov 2.

Association between lipid peroxidation biomarkers and microRNA expression profiles

Yingya Zhao  1 , Marina S Nogueira  2 , Ginger L Milne  3 , Xingyi Guo  4 , Hui Cai  5 , Qing Lan  6 , Nathaniel Rothman  7 , Qiuyin Cai  8 , Yu-Tang Gao  9 , Qingxia Chen  10 , Xiao-Ou Shu  11 , Gong Yang  12
Affiliations

Association between lipid peroxidation biomarkers and microRNA expression profiles

Yingya Zhao et al. Redox Biol. 2022 Dec.

Abstract

Background: In-vitro and animal studies demonstrate that epigenetic regulation may play an important role in lipid peroxidation. No human study to date has directly evaluated microRNAs (miRNAs), as epigenetic modulators, in relation to systemic levels of lipid peroxidation.

Objectives: To evaluate associations between systemic levels of lipid peroxidation and miRNA expression profiles in women.

Methods: Included in the analysis were 92 women aged 40-70 years, a subset of the Shanghai Women's Health Study (SWHS). Lipid peroxidation was assessed by urinary markers F2-isoprostanes (F2-IsoPs), the products of free radical-catalyzed peroxidation of arachidonic acid, and its major metabolite after β-oxidation, 2,3-dinor-5,6-dihydro-15-F2t-IsoP (F2-IsoP-M), with GC/NICI-MS assays. Expression levels of 798 miRNAs were quantified in peripheral plasma with NanoString nCounter assays. A multivariable linear regression model was used to examine the association between lipid peroxidation and miRNA expression.

Results: After adjusting for potential confounders, 29 miRNAs and 213 miRNAs were associated with F2-IsoPs and F2-IsoP-M, respectively. When further controlling for multiple comparisons, none of these nominally significant associations with F2-IsoPs was retained, whereas 71 of 213 miRNAs associated with F2-IsoP-M remained. The predicted targets of the F2-IsoP-M associated miRNAs were enriched for several lipid peroxidation-related processes such as PI3K/AKT, MAPK, FOXO and HIF-1 signaling pathways. Moreover, 10 miRNAs (miR-93-5p, miR-761, miR-301b-3p, miR-497-5p, miR-141-3p, miR-186-5p, miR-126-3p, miR-200b-3p, miR-520d-3p, and miR-363-3p) exhibited functional interactions with 50 unique mRNAs targets involved in the regulation of β-oxidation.

Conclusions: To our knowledge, this study, for the first time, provides human data suggesting that miRNA expression may be linked to lipid peroxidation products and their metabolism.

Keywords: Biomarker; Isoprostanes; Lipid peroxidation; Oxidative stress; microRNA; β-oxidation.

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Conflict of interest statement

Declaration of competing interest None.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Volcano plots capturing significant miRNAs identified by our models for lipid peroxidation biomarkers F2-IsoPs (A) and F2-IsoP-M (B). The horizontal dotted line represents the threshold with a P value of 0.05. Both black and red dots represent miRNAs with P < 0.05, while red dots further denote significant miRNAs with FDR-adjusted P < 0.05. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 2
Heat map representing the expression levels of the 71 miRNAs significantly associated with F2-IsoP-M concentrations. Row z-scores were calculated and color-coded to display miRNA expression, where red indicates higher expression and blue indicates lower expression. Subjects (n = 92) were ordered from the lowest to highest F2-IsoP-M concentration (0.20–1.56 ng/mg Cr) on the x-axis, and miRNAs were clustered on the y-axis using a correlation-based distance method. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
Fig. 3
Functional enrichment analysis. Biological metabolic and signaling pathways enriched for the gene targets of miRNAs significantly associated with urinary concentrations of F2-IsoP-M.
Fig. 4
Fig. 4
Pathway network analysis illustrating the link between the significant miRNAs and biological pathways related to β-oxidation. Ten miRNAs (in red) associated with F2-IsoP-M concentrations and their experimentally validated mRNA targets as identified by the Ingenuity Pathway Analysis software. The biological pathways involved in β-oxidation for miRNA-mRNA interactions are shown in green. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
See this image and copyright information in PMC

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