Book of Abstracts - New Frontiers 2022

Abstracts of oral presentations

FTO INHIBITION IMPAIRS CARDIOMYOCYTE TOLERANCE TO OXYGEN DEPRIVATION

M. Hlavackova 1 , D. Benak 1,2 , D. Sotakova-Kasparova 1 , K. Holzerova 1 , D. Semenovykh 1,2 , L. Sedlakova 1 , S. Skutova 1 , V. Olejnickova 1 , P. Telensky 2,3 , A. Simonova 4 , H. Cahova 4 , A. Pecinova 5 , A. Eckhardt 6 , M. Olsen 7 , J. Neckar 1 , F. Kolar 1 1 Laboratory of Developmental Cardiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic; 2 Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic; 3 International Clinical Research Center of St. Anne‘s University Hospital Brno, Dementia Research Group, Brno, Czech Republic; 4 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic; 5 Laboratory of Bioenergetics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic; 6 Laboratory of Translational Metabolism, Institute of Physiology of the Czech Academy of Sciences, Pague, Czech Republic; 7 Department of Pharmaceutical Sciences, College of Pharmacy-Glendale, Midwestern University, Glendale, Arizona, US Ischemic heart disease is the leading cause of death worldwide. Cardiac tolerance to ischemia can be increased by adaptation to chronic hypoxia, which is associated with significant myocardial gene expression profile changes. Among the possible mechanisms of gene expression alterations are epigenetic modifications of RNA – epitranscriptomics. Our study focused on two of the most prominent marks – N6 methyladenosine (m6A) and N6,2‘ -O-dimethyladenosine (m6Am). We found that m6Am is more abundant in rRNA-depleted RNA isolated from rat cardiomyocytes than m6A. Hypoxic adaptation of rats affected the expression of m6A and m6Am regulators in the heart, including up-regulation of both demethylases – ALKBH5 (m6A) and FTO (m6Am and m6A). Based on these results, we studied the effects of FTO (the only m6Am eraser) inhibition on the proteome, metabolism, and also tolerance to oxygen deprivation of rat cardiomyocytes. FTO inhibition affected protein levels involved in crucial cellular processes such as gene expression, non-coding RNA processing, peptide biosynthesis, and cellular metabolism. Glycolytic and respiration rates of cardiomyocytes were increased after FTO inhibition. Most importantly, we found that FTO inhibition decreases the tolerance of cardiomyocytes to oxygen deprivation in vitro, supporting the possible role of epitranscriptomic regulations in the cardioprotective mechanisms.

Keywords: hypoxia, heart, epitranscriptomics, FTO, m6A, m6Am

Funding: This work was supported by the Czech Science Foundation (grant number 19-04790Y); the Czech Science Foundation (grant number 16-12420Y); the Charles University Grant Agency (grant number GA UK 200317); and the Ministry of Education, Youth and Sports, Czech Republic, program ERC CZ (grant number LL1603).

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