| dc.description.abstracteng | The importance of elucidating mechanisms of cardiac regulatory networks during cardiogenesis is underscored by the re-activation of fetal gene expression in the diseased adult heart. To further understand this phenomenon, the insulin-like growth factor binding protein 5 (IGFBP5), an extracellular binding protein for IGF, possessing IGF-independent functions, was investigated. In this study, analysis of murine cardiac tissue at different developmental stages showed a progressive decrease in Igfbp5 expression with heart maturation, remaining significantly low in the adult heart. Moreover, sustained IGFBP5 expression in human embryonic stem cells arrested cardiomyocyte differentiation subsequent to progenitor specification. In line with these results, expression analysis in different cell populations of the adult murine heart showed very low Igfbp5 expression in cardiomyocytes in contrast to high levels expressed in Sca1-positive cardiac progenitor cells. Additionally, re-expression of IGFBP5 was found in the transition to heart failure in murine and human hearts consequent to pressure overload and aortic stenosis, respectively. Furthermore, IGFBP5 expression detected in mice upon preserved cardiac function post-TAC, was at physiological levels. In the failing heart, cardiomyocytes were shown to express and secrete IGFBP5, which could also be detected in the blood serum. In turn, cardiac fibroblasts showed uptake of exogenous IGFBP5, whereas IGFBP5 overexpression in these cells regulated cardiac gene expression and influenced engineered heart muscle physiology. In vivo, AAV9-mediated cardiomyocyte specific overexpression of Igfbp5 in the adult healthy heart led to an atrophy-like phenotype with reduced heart size. Transcriptome analysis revealed a decrease in extra-cellular matrix and sarcomeric gene expression as well as a reduced junction and ion channel expression, indicating altered cardiac cell integrity. Key regulators of fibrotic processes were downregulated, while a positive effect on fatty acid metabolism could be observed. Notably, this study revealed that IGFBP5 has nuclear functions in cardiac cells including the occupancy of its own promoter and the repression of the TNNT2 promoter by antagonizing NKX2.5-mediated TNNT2 promoter activation. In conclusion, this study demonstrates that IGFBP5 has an important role to play in cardiac progenitor cell commitment and in the transition to heart failure, as a part of the fetal gene re-activation program. Additionally, it furnishes evidence to support an IGFBP5 mediated cardiomyocyte-fibroblast crosstalk, where IGFBP5 may alter gene expression via its transcriptional co-factor function. | de |