Role of non-myocyte NRG1/ERBB4 signaling in cardiac remodeling
22 September 2020
Online defence - - -
4:00 PM - 6:00 PM
Gilles De Keulenaer - Vincent Segers
Phd defence Lindsey Dugaucquier - Department of Pharmaceutical Sciences
Watch the phd defence via Blackboard
In this thesis, we aimed to study ERBB4 signaling in non-myocytes, specifically in ECs and inflammatory cells, and challenge the current concept that the cardiac effects of NRG1 are mediated by paracrine activation of ERBB4/ERBB2 receptors on cardiomyocytes. We studied how NRG1/ERBB4 signaling in ECs or inflammatory cells could contribute to the beneficial effects of NRG1 during cardiac remodeling. The central hypothesis of this thesis is that NRG1/ERBB4 receptor signaling in non-myocytes contributes to the beneficial effects of NRG1 during cardiac remodeling.
Therefore, we first generated mice with myeloid-specific deletion of Erbb4 and tested the effects of myeloid-specific Erbb4 deletion in 2 models of cardiac remodeling—MI and pressure overload. We observed that myeloid-specific Erbb4 deletion accentuated the early increase of myocardial macrophage density in the viable myocardium after MI, but that subsequent ventricular dilation and dysfunction, CM hypertrophy, or interstitial myocardial fibrosis remained unaffected. Interestingly, myeloid-specific Erbb4 deletion reduced infarct scar. In the TAC model, pressure overload–induced myocardial inflammation remained absent, and LV remodeling progressed independently of myeloid ERBB4. Overall, this study shows a modulatory role of NRG1/ERBB4 signaling in myeloid cells during the early inflammatory phase of MI.
Secondly, we generated EC–specific Erbb4 KO mice to specifically eliminate endothelial autocrine ERBB4 signaling without affecting paracrine NRG1/ERBB4 signaling in the heart. First, we observed no basal cardiac phenotype in these mice up to 32 weeks. We next studied these mice following TAC, exposure to Ang II or MI in terms of cardiac performance, myocardial hypertrophy, myocardial fibrosis and capillary density. In general, no major differences between EC–specific Erbb4 KO mice and control littermates were observed. However, 8 weeks following TAC both myocardial hypertrophy and fibrosis were attenuated by EC–specific Erbb4 deletion, albeit these responses were normalized after 20 weeks. Similarly, 4 weeks after Ang II treatment myocardial fibrosis was less pronounced compared to control littermates. These observations were supported by RNA-sequencing experiments on cultured ECs showing that NRG1 controls the expression of various hypertrophic and fibrotic pathways. Overall, these data contribute to our understanding of myocardial cell-cell communication during cardiac remodeling, and to the role of autocrine NRG1/ERBB4 signaling specifically. NRG1 has direct effects on human ECs in vitro, and endothelial autocrine NRG1/ERBB4 signaling plays a role in the modulation of hypertrophic and fibrotic responses during early cardiac remodeling.