| dc.description.abstracteng | Heart failure is a common disease with increasing prevalence. The disease significantly affects quality of life, and mortality and morbidity are high. Current therapies cannot stop the progression of the disease. Therefore, new and more effective therapeutic options are urgently needed. Pathological cardiac hypertrophy is often found as an intermediate step on the way to cardiac insufficiency. In the development of pathological hypertrophy through to cardiac insufficiency, molecular, cellular and interstitial remodeling processes occur, which are referred to as cardiac remodeling. Epigenetic changes also play a role. These epigenetic changes include altered post-transcriptional modifications of RNAs. One of these modifications is the methylation of adenosine at the 6th nitrogen position, m6A for short. N6-methyladenosine is the most common modification in mRNAs. The formation of m6A is catalyzed by the methyltransferase METTL3. In contrast, the demethylase FTO is responsible for removing the modification. In addition, there are various binding proteins of m6A, some of them mediate the functions of the modification. Functions of m6A include affecting pre-mRNA processing, mRNA export, mRNA stability, mRNA structure, and translation. In recent years, it has been increasingly established that m6A plays an important role in the development of heart failure. It was therefore the aim of this work to find out more about the role played by the mRNA modification m6A and its demethylase FTO in the development of hypertrophy up to cardiac insufficiency. To answer this question, the effects of FTO knockdown on endothelin-1-induced hypertrophy were examined in a cardiomyocyte cell culture model. For this purpose, the cardiomyocytes were first differentiated from stem cells. An FTO knockdown was then established in the cardiac muscle cells. In a next step, the FTO knockdown was then combined with an endothelin-1 treatment and its effects on the hypertrophic response of the cells were examined using Western blot and immunofluorescence staining. It was shown that the FTO knockdown weakens the hypertrophic response of the cardiomyocytes. Moreover, it was shown that the amount of the ERK1/2 protein, a protein of an endothelin-1-induced signaling pathway, is not altered by the FTO deficiency. In addition, endothelin-1 stimulation had no effect on the amount of FTO protein. Taken together, the results of this work suggest that FTO plays a crucial role in the response to cardiac stress. The protein is significantly involved in the development of (concentric) hypertrophy. FTO deficiency prevents cardiomyocyte hypertrophy. This effect of the FTO deficiency appears to be mediated through m6A. In contrast, impairment of the ERK1/2 signaling pathway activated by endothelin-1 does not seem to play a role. The FTO deficiency presumably results in m6A hypermethylation and in particular in an altered m6A methylation pattern. As a result, pre-mRNA processing, mRNA export, mRNA stability, mRNA structure, or translation are likely to be affected. This could explain the lack of synthesis of the hypertrophic proteins and thus the weakening of the hypertrophic response of the heart muscle cells. Overall, the findings of this work indicate that FTO is involved in the regulation of cardiac remodeling. Therefore, a controlled intervention in the FTO regulation could open up new therapy options for heart failure in the future. | de |