NAT10 promotes aortic aneurysms through lysine acetylation modification

Abstract Background The phenotypic switch of vascular smooth muscle cell (VSMC) is a fundamental pathological process implicated in various vascular diseases, including vascular remodeling and aortic aneurysm (AA). Previous studies have demonstrated that NAT10 modulates the VSMC phenotypic switch, thereby facilitating vascular neointima formation. Nevertheless, the biological functions and regulatory mechanisms of NAT10 in the context of AA development remain inadequately understood. Methods To elucidate the role of NAT10 in AA development, we employed VSMC-specific NAT10-knockout mice in models of AA induced by angiotensin II (Ang II) and β-aminopropionitrile (BAPN). The potential mechanisms by which NAT10 influences AA were investigated using NAT10 immunoprecipitation mass spectrometry, acetylomics, and proteomics analyses. Result Our investigation revealed that the expression levels of NAT10 and protein acetylation (KAc) were markedly elevated in both human and murine AA samples. Furthermore, in models of AA induced by Ang II and BAPN, the formation of AA was significantly attenuated in mice with a knockout of NAT10 in VSMC. Mechanistic studies identified that NAT10 interacts with key enzymes related to the mitochondrial tricarboxylic acid cycle, including pyruvate dehydrogenase, aconitase-2, and isocitrate dehydrogenase, and downregulates their expression through KAc in VSMC. Administration of the NAT10 inhibitor, Remodelin, effectively prevented and treated AA in mice. Conclusion Our studies reveal the mechanism of KAc modification in regulating the formation of AA from an epigenetic perspective, which is expected to provide new ideas for the prevention and treatment of AA in clinical practice and is of great significance.