机构：[1]Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China[2]Shanghai Eye Diseases Prevention and Treatment Center, Shanghai Eye Hospital, Shanghai General Hospital, National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China[3]Department of Endocrinology and Metabolism, Shanghai 10th People’s Hospital, School of Medicine, Tongji University, Shanghai, China.[4]present address: Division of Ophthalmology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China.[5]present address: Department of Ophthalmology, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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 Fto Delta/Delta) 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-KB 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-KB network provides potential targets to treat diabetic vascular complications.
基金：
National Science and Technology Major Project of China [2017ZX09304010]; National Natural Science Foundation of China [82271111, 82002891, 82170904]; Shanghai Science and Technology Development Foundation [22QA1407500]; Shanghai Rising Stars of Medical Talent Youth Development Program [2022-65]; Clinical Research Innovation Plan of Shanghai General Hospital [CTCCR-2021C01]; Natural Science Foundation of Shanghai [20ZR1445600]
第一作者机构：[1]Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China[3]Department of Endocrinology and Metabolism, Shanghai 10th People’s Hospital, School of Medicine, Tongji University, Shanghai, China.[*1]No. 100 Haining Road, Hongkou District, Shanghai, China.[*2]No. 301 Middle Yanchang Road, Shanghai, China.
推荐引用方式(GB/T 7714)：
Zhou Chuandi,She Xinping,Gu Chufeng,et al.FTO fuels diabetes-induced vascular endothelial dysfunction associated with inflammation by erasing m6A methylation of TNIP1[J].JOURNAL OF CLINICAL INVESTIGATION.2023,133(19):doi:10.1172/JCI160517.
APA：
Zhou, Chuandi,She, Xinping,Gu, Chufeng,Hu, Yanan,Ma, Mingming...&Zheng, Zhi.(2023).FTO fuels diabetes-induced vascular endothelial dysfunction associated with inflammation by erasing m6A methylation of TNIP1.JOURNAL OF CLINICAL INVESTIGATION,133,(19)
MLA：
Zhou, Chuandi,et al."FTO fuels diabetes-induced vascular endothelial dysfunction associated with inflammation by erasing m6A methylation of TNIP1".JOURNAL OF CLINICAL INVESTIGATION 133..19(2023)
医学