Fto deficiency reduces infarct size and improves heart function after acute myocardial infarction

Abstract

Obesity is one of the major risk factors that can lead to a myocardial infarction and can negatively influence subsequent cardiac remodeling. The onset of obesity is related to different genetic variants of the fat mass and obesity associated gene (Fto). Fto deficient mice were protected from obesity and showed an improved glucose tolerance under a high fat diet. In addition, it is known that Fto acts as an m6A RNA demethylase, whereby it can influence mRNA stability and translation. In a first approach, we used Fto deficient mice to perform an ischemic/reperfusion (I/R) model. At 24 h after reperfusion, Fto deficient mice already had a smaller infarct size compared to their wild type littermates. Over a time period of three weeks, the heart function was investigated by echocardiography. Three weeks after reperfusion, Fto deficient mice showed a preserved heart function and had reduced collagen scar formation compared to wild‐type control mice. Initial molecular studies indicated a reduction of the mTORC1 pathway and consequently a down regulation of S6K phosphorylation. For a first approach of therapeutic intervention, we used the Fto inhibitor rhein, which binds the active center of Fto and thereby inhibits its demethylase activity. Wild type mice were pre‐treated with rhein or the solvent over three weeks before the I/R procedure was performed. The rhein‐treated mice showed a significant reduction in the infarct size compared to the solvent treated littermates. In this study, we demonstrated that Fto deficiency can modulate the outcome of a myocardial infarction by improving left ventricular function and reduction of the infarct size.Support or Funding InformationSupported by the Deutsche Forschung Gesellschaft (DFG) as Part of the SFB 1116 (project number 236177352)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.