Impact of GATA transcription factors on mechanical load dependent myocardial fibroblast activation, migration and protective paracrine signalling in heart disease

心肌成纤维细胞在心脏负荷时转变为肌成纤维细胞，并通过分泌细胞外基质和生长因子作为限制组织损伤的第一反应者。另一方面，它们促进病理性纤维化的发展，从而引发心功能障碍。我们假设GATA4和GATA6在慢性心脏负荷时充当压力传感器，并协调心肌成纤维细胞的机械反应，如慢性动脉高血压或主动脉瓣狭窄患者。为了验证我们的假设，我们产生了成纤维细胞特异性GATA4、GATA6和GATA4/GATA6化合物敲除小鼠。我们将研究这些成纤维细胞GATA因子对肌成纤维细胞功能和基因表达的影响，以及在实验性横主动脉收缩引起的压力过载时对心脏重塑和功能的影响。此外，我们将分析导致成纤维细胞GATA激活的信号机制以及这些细胞中GATA依赖转录的机制。

Cardiac fibroblasts turn into myofibroblasts during cardiac overload and act as first responders to limit tissue injury by secreting extracellular matrix and growth factors. On the other hand they contribute to the development of pathological fibrosis and thereby trigger cardiac dysfunction. We hypothesize that GATA4 and GATA6 act as stress sensors and coordinate the mechanoresponse in cardiac myofibroblasts during chronic cardiac overload as it occurs for example in patients with chronic arterial hypertension or aortic valve stenosis. In order to examine our hypothesis, we are generating fibroblast specific GATA4, GATA6 and GATA4/GATA6 compound knock-out mice. We will investigate the impact of these fibroblast GATA factors on myofibroblasts function and gene-expression as well as on cardiac remodelling and function during pressure overload due to experimental transverse aortic constriction. In addition, we will analyze the signalling mechanisms leading to fibroblast GATA activation as well as the mechanisms of GATA dependent transcription in these cells.