Does YAP/TAZ signalling play a role in right-left ventricular interactions?
Final Report Abstract
My research fellowship focused on the question if YAP/TAZ signaling plays a role in right-left ventricular interactions. My results clearly answer this question: As shown in our animal models, rats subjected to PAB display elevated expression of MRTF-A and YAP/TAZ alongside RV fibrosis, depressed functional parameters and elevated cardiomyocyte hypertrophy, all events which were attenuated in the presence of pharmacological MRTF-A inhibition. Moreover, MRTF-A is critical in driving RV fibroblast expression of TAZ and markers of myofibroblast activation in response to TGF-β1 stress and RhoA activation, with inhibition of RhoA also reducing RV fibroblast pro-fibrotic gene expression and myofibroblast activation. Our results showcase that RhoA, MRTF-A, and YAP/TAZ are interconnected regulators of pro-fibrotic signaling in RV pressure-loading, and their potential targeting may help improve RV functional parameters by limiting RV fibrosis burden. In addition to these findings, we have demonstrated that double banding surgery prevents the development of these maladaptive features as demonstrated by PSR staining, and heart weights. These findings were consistent with our previously published work in rabbits, however here we demonstrate that the degree of aortic constriction significantly impacts the attenuation of RV remodeling. Although the course of my projects has been significantly compromised by the COVID-19 pandemia, I was able to complete my research project, although publication of my results is still pending.
