Dataset Information

MiR-155 down-regulation protects the heart from hypoxic damage by activating fructose metabolism in cardiac fibroblasts.

ABSTRACT:

Introduction

Hypoxia-inducible factor (HIF)1α has been shown to be activated and induces a glycolytic shift under hypoxic condition, however, little attention was paid to the role of HIF1α-actuated fructolysis in hypoxia-induced heart injury.

Objectives

In this study, we aim to explore the molecular mechanisms of miR-155-mediated fructose metabolism in hypoxic cardiac fibroblasts (CFs).

Methods

Immunostaining, western blot and quantitative real-time reverse transcription PCR (qRT-PCR) were performed to detect the expression of glucose transporter 5 (GLUT5), ketohexokinase (KHK)-A and KHK-C in miR-155^-/- and miR-155^wt CFs under normoxia or hypoxia. A microarray analysis of circRNAs was performed to identify circHIF1α. Then CoIP, RIP and mass spectrometry analysis were performed and identified SKIV2L2 (MTR4) and transformer 2 alpha (TRA2A), a member of the transformer 2 homolog family. pAd-SKIV2L2 was administrated after coronary artery ligation to investigate whether SKIV2L2 can provide a protective effect on the infarcted heart.

Results

When both miR-155^-/- and miR-155^wt CFs were exposed to hypoxia for 24 h, these two cells exhibited an increased glycolysis and decreased glycogen synthesis, and the expression of KHK-A and KHK-C, the central fructose-metabolizing enzyme, was upregulated. Mechanistically, miR-155 deletion in CFs enhanced SKIV2L2 expression and its interaction with TRA2A, which suppresses the alternative splicing of HIF1α pre-mRNA to form circHIF1α, and then decreased circHIF1α contributed to the activation of fructose metabolism through increasing the production of the KHK-C isoform. Finally, exogenous delivery of SKIV2L2 reduced myocardial damage in the infarcted heart.

Conclusion

In this study, we demonstrated that miR-155 deletion facilitates the activation of fructose metabolism in hypoxic CFs through regulating alternative splicing of HIF1α pre-mRNA and thus circHIF1ɑ formation.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC9263644 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Publications

miR-155 down-regulation protects the heart from hypoxic damage by activating fructose metabolism in cardiac fibroblasts.

Zhang Yu Y Zhang Hong H Yang Zhan Z Zhang Xin-Hua XH Miao Qing Q Li Min M Zhai Tian-Ying TY Zheng Bin B Wen Jin-Kun JK

Journal of advanced research 20211020

<h4>Introduction</h4>Hypoxia-inducible factor (HIF)1α has been shown to be activated and induces a glycolytic shift under hypoxic condition, however, little attention was paid to the role of HIF1α-actuated fructolysis in hypoxia-induced heart injury.<h4>Objectives</h4>In this study, we aim to explore the molecular mechanisms of miR-155-mediated fructose metabolism in hypoxic cardiac fibroblasts (CFs).<h4>Methods</h4>Immunostaining, western blot and quantitative real-time reverse transcription PC ...[more]

PMID: 35777901

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