Abstract

N 6 -methyladenosine (m 6 A) is one of the most abundant methylation modifications in mRNA, regulating different stages of mRNA metabolism, including folding, maturation, export, translation, and decay. However, the role of m 6 A modification and the m 6 A demethylase fat mass and obesity-associated (FTO) in abdominal aortic aneurysms (AAAs) remains unclear. We found that FTO expression levels were elevated in both in vitro and in vivo models of abdominal aortic aneurysms, and silencing FTO could partially reverse AngII-induced apoptosis of vascular smooth muscle cells (VSMCs). Integrated RNA-seq and MeRIP-seq analysis further identified pyruvate dehydrogenase kinase 4 (PDK4) as the target gene of FTO-mediated m 6 A modification. FTO mediates m 6 A demethylation in the 3’ untranslated region (3’ UTR) of PDK4 mRNA and induces its degradation through a YTH N 6 -methyladenosine RNA binding protein 2 (YTHDF2)-dependent mechanism. Overexpression of PDK4—a key enzyme in mitochondrial glucose metabolism and a novel regulator of mitochondria-associated endoplasmic reticulum integrity—reversed the inhibitory effect on apoptosis after FTO silencing. These results suggest that FTO regulates VSMC apoptosis by mediating m 6 A demethylation of PDK4 mRNA and promoting its degradation in a YTHDF2-dependent manner. Moreover, PDK4 overexpression reverses the apoptosis-inhibitory effect induced by FTO silencing.