Villalba-Orero, M. | Search bioRxiv

bioRxiv2020

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ after myocardial infarction

Macrophages produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. In this study, we demonstrated that cardiac macrophages increased expression of Mmp14 (MT1-MMP) 7 days post-MI. Specific macrophage-targeting of MT1-MMP (MT1-MMP{Delta}LysM mice) attenuates post-MI cardiac dysfunction, reduces fibrosis, and preserves the cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGF{beta}1 in macrophages, leading to paracrine SMAD2-mediated signaling in endothelial cells and endothelial-to-mesenchymal transition (EndMT). Post-MI MT1-MMP{Delta}LysM hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and MT1-MMP-deficient macrophages showed a reduced ability to induce EndMT in co-cultures with endothelial cells. Our results demonstrate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify macrophage MT1-MMP as a key regulator of this process. The identified mechanism has potential as a therapeutic target in ischemic heart disease.

immunology↗

bioRxiv2020

Functional impact and regulation of global alternative splicing patterns in heart development and disease

Alternative splicing (AS) plays a major role in the generation of transcript diversity. In the heart, roles have been described for some AS variants and individual regulatory RNA binding proteins (RBPs); however, the global impact and regulation of AS patterns in cardiac pathophysiology is poorly understood. Here, we studied the AS profiles in heart disease, their relationship with heart development and the regulatory mechanisms control-ling AS dynamics in the mouse heart using a total of 136 RNA-seq samples. We found that AS and gene expression changes affect different genes, which are also involved in distinct biological functions. Developmental AS changes were more abundant and had stronger predicted impact on the encoded protein than those taking place during heart disease. However, AS changes in heart disease significantly modified protein interaction patterns and rewire the protein-protein interaction network. Using a database of experimentally determined binding sites of a large collection of RNA binding proteins, we studied the regulatory proteins associated to AS changes in each condition. Computational modelling revealed that developmental transitions were mainly driven by the up-regulation of MBNL1, whereas disease associated AS changes were driven by a more complex regulatory network, characterized by the interaction of different RNA binding proteins, with PTBP1 as the largest individual modulator. In adult mice, PTBP1 over-expression was sufficient to induce cardiac hypertrophy and diastolic dysfunction and significantly alter the AS profile. Overall, our study provides new in-sights into the functional impact of AS patterns in cardiac physiology and how computationally driven hypotheses can help to improve our understanding of RNA regulation and its contribution to heart disease.

bioinformatics↗