%0 Generic
%A Sandmann, Christoph
%C Heidelberg
%D 2024
%F heidok:35569
%R 10.11588/heidok.00035569
%T Translational Control of an Inflammatory Network in the Heart
%U https://archiv.ub.uni-heidelberg.de/volltextserver/35569/
%X In this thesis I investigated a previously unrecognized translational burst of the infarct and border zone after cardiac reperfusion in a mouse model of ischemia/reperfusion injury. This translational response is mediated partly by border zone cardiomyocytes, which increasingly translate mRNAs related to inflammation and cell migration in response to reperfusion. Among those increasingly translated transcripts is the mRNA that encodes C-C Motif Chemokine Ligand 2 (CCL2), a chemokine that is involved in the attraction of monocytes to the injured heart. A transient pharmacological inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) - eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) - eukaryotic translation initiation factor 4E (eIF4E) axis, which I found to be involved in the translational activation of border zone cardiomyocytes, inhibited myocardial inflammatory, monocyte infiltration, improved cardiac contractility, reduced infarct size, and strongly suppressed cardiac Ccl2 expression and release from the infarcted heart in a preclinical model of ischemia/reperfusion in mice. Reduced Ccl2 gene expression after inhibition of the mTORC1-4EBP1-eIF4E axis was at least partly derived from attenuated translation of the Ccl2 transcript. In addition, a direct inhibitory effect of rapamycin and 4EGI-1, pharmacological inhibitors of mTORC1-dependent translation, on circulating monocytes was observed, which may contribute to the attenuation of inflammatory monocyte infiltration into the infarcted heart after mTORC1-4EBP1-eIF4E axis inhibition. Improved cardiac function after pharmacological mTORC1-4EBP1-eIF4E axis inhibition may thus result from the attenuation of a pro-inflammatory translational network, involving the inhibition of translation of the mRNA encoding for the chemokine CCL2 by border zone cardiomyocytes, as well as a direct inhibitory effect on circulating monocytes, thus attenuating maladaptive aspects of cardiac inflammation and remodeling after myocardial infarction and reperfusion.