title: Triazole RGD antagonist reverts TGFβ1-induced endothelial-to-mesenchymal transition in endothelial precursor cells.
abstract: Fibrosis is the dramatic consequence of a dysregulated reparative process in which activated fibroblasts (myofibroblasts) and Transforming Growth Factor β1 (TGFβ1) play a central role. When exposed to TGFβ1, fibroblast and epithelial cells differentiate in myofibroblasts; in addition, endothelial cells may undergo endothelial-to-mesenchymal transition (EndoMT) and actively participate to the progression of fibrosis. Recently, the role of αv integrins, which recognize the Arg-Gly-Asp (RGD) tripeptide, in the release and signal transduction activation of TGFβ1 became evident. In this study, we present a class of triazole-derived RGD antagonists that interact with αvβ3 integrin. Above different compounds, the RGD-2 specifically interferes with integrin-dependent TGFβ1 EndoMT in Endothelial Colony-Forming Cells (ECPCs) derived from circulating Endothelial Precursor Cells (ECPCs). The RGD-2 decreases the amount of membrane-associated TGFβ1, and reduces both ALK5/TGFβ1 type I receptor expression and Smad2 phosphorylation in ECPCs. We found that RGD-2 antagonist reverts EndoMT, reducing α-smooth muscle actin (α-SMA) and vimentin expression in differentiated ECPCs. Our results outline the critical role of integrin in fibrosis progression and account for the opportunity of using integrins as target for anti-fibrotic therapeutic treatment.
authors.affiliation: Department of Clinical and Experimental Biomedical Science "Mario Serio", University of Florence, Florence, Italy. francesca.bianchini@unifi.it.
authors.forename: Francesca
authors.identifier: http://orcid.org/0000-0002-5839-4298
authors.initials: F
authors.lastname: Bianchini
authors.affiliation: Department of Clinical and Experimental Biomedical Science "Mario Serio", University of Florence, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Peppicelli
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Florence, Italy.
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Fabbrizzi
authors.affiliation: Department of Clinical and Experimental Biomedical Science "Mario Serio", University of Florence, Florence, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Biagioni
authors.affiliation: Cord Blood Bank, Careggi University Hospital, Florence, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mazzanti
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Florence, Italy.|Interdepartmental Center for Preclinical Development of Molecular Imaging (CISPIM), University of Florence, Florence, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Menchi
authors.affiliation: Department of Clinical and Experimental Biomedical Science "Mario Serio", University of Florence, Florence, Italy.
authors.forename: Lido
authors.initials: L
authors.lastname: Calorini
authors.affiliation: Department of Clinical and Experimental Biomedical Science "Mario Serio", University of Florence, Florence, Italy.|Interdepartmental Center for Preclinical Development of Molecular Imaging (CISPIM), University of Florence, Florence, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Pupi
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, Florence, Italy.|Interdepartmental Center for Preclinical Development of Molecular Imaging (CISPIM), University of Florence, Florence, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Trabocchi
mesh_terms: D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis; D009842:Oligopeptides / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis; D051899:Smad2 Protein / Q000096:biosynthesis; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014230:Triazoles / Q000737:chemistry
chemical_list: D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D014230:Triazoles; C047981:arginyl-glycyl-aspartic acid; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human
keywords: Endothelial Colony-Forming Cells (ECPCs); Endothelial-to-Mesenchymal Transition (EMT); Fibrosis; Transforming Growth Factorβ1 (TGFβ1); αvβ3 integrin