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

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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.