Upon cardiac stress, for example by pressure overload (PO) from aortic stenosis, growth of cardiomyocytes (CMs) occurs. This initial hypertrophic adaptation preserves cardiac performance. Persistent hemodynamic stress leads to decompensation of the heart resulting in heart failure. Treatment options concentrate on inhibition of neuroendocrine stimulation or deregulated signaling pathways, but this has only limited efficacy and the morbidity and mortality of HF patients remains high. Therefore, other therapeutic options need to be investigated. Aberrant gene expression, such as re-expression of the fetal gene program, is a key-event in HF progression. Recent research suggested that changes in gene expression are not only regulated by transcription factors, but also by epigenetic processes such as non-coding RNAs and histone or DNA modifications. Another less studied epigenetic modification is RNA methylation. The most prevalent modification is methylation of the adenosine base, termed m6A methylation. This m6A methylation is a dynamic and reversible process, mediated by so-called ‘writer’ and ‘eraser’ proteins adding or removing methylation marks on RNA. RNA methylation can affect splicing, mRNA transport, translation, storage, or decay. These effects were shown to be either mediated directly by conformational changes of methylated RNA or by so called ‘reader’ proteins, which recognize methylation marks. This adds an additional layer of transcriptional and translational control.

In our study, we tried to evaluate the effect of a manipulation of the methylation machinery on the development and progression to heart failure. We investigated the effect of manipulation of the RNA demethylase FTO on hypertrophic responses in vitro and in -vivo. For in vitro studies, a human induced pluripotent stem cell (iPSC) model was used. iPSCs were differentiated to beating cardiomyocytes (iPSC-CMs), and hypertrophic growth was induced via Endothelin-1 (ET-1) treatment together with siRNA mediated silencing of FTO. We observed that cell growth was attenuated upon silencing of FTO and expression of the stress-marker ANP was reduced. To determine, how the demonstrated in-vitro effect presents in vivo, a cardiomyocyte specific Fto knockout (KO) was bred and a transverse aortic constriction (TAC) model was applied to investigate hypertrophy and heart failure in FTO-deficient mice in response to PO. Intriguingly, KO mice show a maladaptive response to PO, with early onset of dilatation and significantly impaired cardiac function compared to control mice.

Therefore, we hypothesize that the attenuated hypertrophy observed in vitro represents the inability of FTO-depleted CMs to undergo initial compensatory adaptation as seen in the in vivo model. Together, our findings underline the importance of m6A RNA methylation in cardiac hypertrophy and heart failure progression and provide insight into the manipulation of FTO as a potential therapy in pressure overloaded hearts.