AUTHOR=Ma Dong , Liu Xiao , Zhang Jin-jin , Zhao Jun-jian , Xiong Yan-jie , Chang Quan , Wang Hong-yan , Su Peng , Meng Jia , Zhao Yong-bo 

TITLE=Vascular Smooth Muscle FTO Promotes Aortic Dissecting Aneurysms via m6A Modification of Klf5

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 7 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2020.592550

DOI=10.3389/fcvm.2020.592550

ISSN=2297-055X

ABSTRACT=Background Aortic dissecting aneurysm (ADA) represents an aortic remodeling disease with a high mortality rate. Fat mass and obesity-associated protein (FTO) exerts RNA demethylation function to regulate gene expression related to stem cell differentiation, DNA damage repair and tumorigenesis. However, the role of FTO in ADA remains unknown. 
Methods The expression and location of FTO in 43 ADA tissues and 11 normal tissues were determined by RT-qPCR, WB, immunohistochemistry and immunofluorescence staining. Detecting proliferation and migration of VSMCs. M6A methylated RNA immuno-precipitation qRT-PCR and dual luciferase reporter assay were performed for determining m6A level and interaction between m6A modulation and Klf5 mRNA respectively. 
Results FTO is highly expressed in VSMCs. FTO was positively correlated with BMI, triglyceride, and D-dimer (all P < 0.05). Functionally, both AngII-induced FTO expression and overexpression of FTO promote cell proliferation and migration, whereas knockdown of FTO inhibits these functions. Mechanically, we identified Krüppel-like factor 5 (Klf5) is a target of FTO mediating m6A modification. Overexpression of FTO reduced m6A modification on Klf5 mRNA and promoted Klf5 mRNA expression. Furthermore, p-GSK3β and Klf5 levels increased after FTO overexpression. Finally, knockdown of FTO suppresses p-GSK3β levels and Klf5 expression regardless of AngII treatment. 
Conclusions Our study revealed the demethylation function (m6A) of FTO plays an essential role in the phenotype conversion of VSMCs and the ADA, thereby providing a novel therapeutic target.