FTO fuels diabetes-induced vascular endothelial dysfunction associated with inflammation by erasing m6A methylation of TNIP1
Chuandi Zhou, … , Haibing Chen, Zhi Zheng
Chuandi Zhou, … , Haibing Chen, Zhi Zheng
Published October 2, 2023
Citation Information: J Clin Invest. 2023;133(19):e160517. https://doi.org/10.1172/JCI160517.
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Research Article Inflammation Vascular biology

FTO fuels diabetes-induced vascular endothelial dysfunction associated with inflammation by erasing m6A methylation of TNIP1

Abstract

Endothelial dysfunction is a critical and initiating factor of the vascular complications of diabetes. Inflammation plays an important role in endothelial dysfunction regulated by epigenetic modifications. N6-methyladenosine (m6A) is one of the most prevalent epigenetic modifications in eukaryotic cells. In this research, we identified an m6A demethylase, fat mass and obesity-associated protein (FTO), as an essential epitranscriptomic regulator in diabetes-induced vascular endothelial dysfunction. We showed that enhanced FTO reduced the global level of m6A in hyperglycemia. FTO knockdown in endothelial cells (ECs) resulted in less inflammation and compromised ability of migration and tube formation. Compared with EC Ftofl/fl diabetic mice, EC-specific Fto-deficient (EC FtoΔ/Δ) diabetic mice displayed less retinal vascular leakage and acellular capillary formation. Furthermore, methylated RNA immunoprecipitation sequencing (MeRIP-Seq) combined with RNA-Seq indicated that Tnip1 served as a downstream target of FTO. Luciferase activity assays and RNA pull-down demonstrated that FTO repressed TNIP1 mRNA expression by erasing its m6A methylation. In addition, TNIP1 depletion activated NF-κB and other inflammatory factors, which aggravated retinal vascular leakage and acellular capillary formation, while sustained expression of Tnip1 by intravitreal injection of adeno-associated virus alleviated endothelial impairments. These findings suggest that the FTO-TNIP1-NF-κB network provides potential targets to treat diabetic vascular complications.

Authors

Chuandi Zhou, Xinping She, Chufeng Gu, Yanan Hu, Mingming Ma, Qinghua Qiu, Tao Sun, Xun Xu, Haibing Chen, Zhi Zheng

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Figure 6

The FTO-TNIP1-NF-κB network regulates diabetes-induced retinal vascular endothelial dysfunction.

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The FTO-TNIP1-NF-κB network regulates diabetes-induced retinal vascular ...
(A) Western blotting displaying higher TNIP1 expression and lower NF-κB expression in the retinas of endothelial cell–specific (EC-specific) Fto-deficient (EC FtoΔ/Δ) mice as compared with EC Ftofl/fl mice (n = 3). (B) Western blotting indicating that TNIP1 was inversely correlated with FTO expression, while the expression of NF-κB positively changed with FTO (n = 3). (C) Silencing Tnip1 by the intravitreal injection of adeno-associated virus (AAV) vectors containing siRNA-Tnip1 increased retinal vascular leakage in EC FtoΔ/Δ mice (n = 4, scale bar: 1 mm). (D) Silencing Tnip1 by the intravitreal injection of AAV vectors containing siRNA-Tnip1 increased the number of acellular capillaries in EC FtoΔ/Δ mice (n = 4, scale bar: 50 μm). (E) Immunofluorescence showing that downregulated FTO suppressed NF-κB, and this trend was reversed by silencing TNIP1 (n = 4, scale bar: 100 μm). Significant differences were assessed by 1-way ANOVA followed by Bonferroni’s post hoc comparison test. Data are shown as the mean ± SD. *P < 0.05.