119 Moreover, this study determined that several miR-21 mRNA targets were differentially expressed purchase Capecitabine during fibrogenic EMT of EMCs, such as PDCD4 and SPRY1, of which miR-21-dependent suppression contributed to the development of the fibroblast-like phenotype of EMCs. 119 Another study of the same group utilized TGF beta-induced EMT in rat-derived adult EMC cultures to investigate the role of Islet-1 (Isl1), a known marker of progenitor cells such as EMCs. They reported that Isl1

promoted the mesenchymal phenotype in untreated EMCs, whilst during TGF beta-induced EMT Isl1 was underexpressed, exerting a negative effect on EMT progression. The observed underexpression of Isl1 was in part attributable to miR-31, which was shown to act as a negative modulator of cardiac fibrogenic EMT, primarily via targeting Isl1. 120 Overall, these studies shed light to molecular mechanisms implicated in the contribution of EMCs to cardiac fibrosis, whilst suggesting a regulatory role for miR-21 and miR-31 in the fibrogenic EMT of EMCs. According to recent studies, endothelial cells can also provide fibroblast-like cells through endothelial-to–mesenchymal transition (EndMT), but the presence of cells of this origin in the adult myocardium occurs only under pathological conditions and is associated with fibrosis. 121 Zeisberg and partners suggested that endothelial cells may undergo (EndMT) and generate CFs, and they

showed that EndMT contributes to cardiac fibrosis progression in mouse models of pressure overload and chronic allograft rejection. 122 More recently, Ghosh et al reported differential expression of several miRs during cardiac EndMT. 123 Specifically, they treated cultured mouse cardiac endothelial cells (MCECs) with TGFbeta2 to trigger EndMT, and performed microRNA microarrays to measure total microRNA expression

in fibroblast-like cells vs MCECs. They reported significant expression changes in a range of miRs in fibroblast-like cells, and amongst them there were many previously associated with CVD ( ↑ miR-125b, -21, -30b,-195, Let-7c, -7g; ↓ miR-122a, -127, -196, -375). The expression of miR-125b was further validated by qPCR, whilst the protein levels of its target p53 were found downregulated in the EndMT-derived fibroblast-like cells. Interestingly, p53 is known to antagonize TGFbeta-induced profibrotic responses, 124 therefore miR-125b overexpression may lead to profibrotic signaling Cilengitide upregulation via suppressing its target p53 in these fibroblast-like cells. In conclusion, EndMT-derived fibroblast-like cells emerge as a novel cardiac fibrosis mediators, whilst their disease-specific existence in the adult myocardium may facilitate the development of miRNA based tools to target fibrosis. miRNAs impact on calcium cycling The dysregulation of miR-1 and -133a appears to serve multiple and distinct roles during HF development and progression.