Transcriptional regulation of endothelial-to-mesenchymal transition in cardiac fibrosis: role of myocardin-related transcription factor A and activating transcription factor 3

Abstract

The etiology of cardiac fibrogenesis is quite diverse, but a common feature is the presence of activated fibroblasts. Experimental evidence suggests that a subset of cardiac fibroblasts is derived via transition of vascular endothelial cells into fibroblasts by endothelial-to-mesenchymal transition (EndMT). During EndMT, endothelial cells lose their endothelial characteristics and acquire a mesenchymal phenotype. Molecular mechanisms and the transcriptional mediators controlling EndMT in heart during development or disease remain relatively undefined. Myocardin-related transcription factor A facilitates the transcription of cytoskeletal genes by serum response factor during fibrosis; therefore, its specific role in cardiac EndMT might be of importance. Activation of activating transcription factor 3 (ATF-3) during cardiac EndMT is speculative, since ATF-3 responds to a transforming growth factor β (TGF-β) stimulus and controls the expression of the primary epithelial-to-mesenchymal transition markers Snail, Slug, and Twist. Although the role of TGF-β in EndMT-mediated cardiac fibrosis has been established, targeting of the TGF-β ligand has not proven to be a viable anti-fibrotic strategy owing to the broad functional importance of this ligand. Thus, targeting of downstream transcriptional mediators may be a useful therapeutic approach in attenuating cardiac fibrosis. Here, we discuss some of the transcription factors that may regulate EndMT-mediated cardiac fibrosis and their involvement in type 2 diabetes.

Gemigliptin Inhibits Interleukin-1β–Induced Endothelial-Mesenchymal Transition via Canonical-Bone Morphogenetic Protein Pathway

“…Furthermore, Foxm1 bound to and increased the promoter activity of the Snail gene, which encodes a critical transcriptional regulator of the EndMT [27]. ATF-3 responds to TGF-β and controls the expression of the primary epithelial-to-mesenchymal transition markers, Snail, Slug, and Twist [28]. These three transcription factors are thought to be associated with TGF-β-induced EndMT.…”

miR‐222 inhibits cardiac fibrosis in diabetic mice heart via regulating Wnt/β‐catenin‐mediated endothelium to mesenchymal transition

“…miR-222 overexpression ameliorated cardiac fibrosis Fibrosis is a process in which fibroblasts are overactivated and extracellular matrix proteins are deposited, leading to cardiac remodeling and dysfunction (Frangogiannis, 2019). Fibroblasts are the major collagen-producing cells, and continuous stimulation under pathological conditions leads to their overactivation and the overproduction of collagen (Sharma, Dogra, Saikia, & Khullar, 2017). A recent study reported that in aortic stenosis patients, miRNA-222 levels were negatively related with myocardial fibrosis (Verjans et al, 2018).…”

Effects of the (Pro)renin Receptor on Cardiac Remodeling and Function in a Rat Alcoholic Cardiomyopathy Model via the PRR-ERK1/2-NOX4 Pathway

“…In a mouse model of ischemia-reperfusion injury, overexpression of PRR aggravated renal inflammation and fibrotic lesions by amplifying Wnt/ β -catenin signaling rather than relying on Ang II [32]. In postmyocardial infarct hearts, PRR increased myocardial fibrosis and worsened cardiac function, and these effects did not depend on Ang II [34].…”