: Cardiac stromal cells (CSCs) are the main players in fibrosis. Dysmetabolic conditions (metabolic syndrome - MetS, and type 2 diabetes - DM2) are strong pathogenetic contributors to cardiac fibrosis. Moreover, modulation of the oxidative state (OxSt) and autophagy is a fundamental function affecting the fibrotic commitment of CSCs, that are adversely modulated in MetS/DM2. We aimed to characterize CSCs from dysmetabolic patients, and to obtain a beneficial phenotypic setback from such fibrotic commitment by modulation of OxSt and autophagy. CSCs were isolated from 38 patients, stratified as MetS, DM2, or controls. Pharmacological modulation of OxSt and autophagy was obtained by treatment with trehalose and NOX4/NOX5 inhibitors (TREiNOX). Flow-cytometry and RT-qPCR analyses showed significantly increased expression of myofibroblasts markers in MetS-CSCs at baseline (GATA4, ACTA2, THY1/CD90) and after starvation (COL1A1, COL3A1). MetS- and DM2-CSCs displayed a paracrine profile distinct from control cells, as evidenced by heatmap analysis of 30 secreted cytokines, with significant reduction in VEGF and endoglin confirmed by ELISA. DM2-CSCs showed significantly reduced support to endothelial cells in angiogenic assays, and significantly increased H2 O2 release and NOX4/5 expression levels. Autophagy impairment after starvation (reduced ATG7 and LC3-II proteins) was also detectable in DM2-CSCs. TREiNOX treatment significantly reduced ACTA2, COL1A1, COL3A1, and NOX4 expression in both DM2- and MetS-CSCs, as well as GATA4 and THY1/CD90 in DM2, all versus control cells. Moreover, TREiNOX significantly increased VEGF release by DM2-CSCs, and VEGF and endoglin release by both MetS- and DM2-CSCs, also recovering the angiogenic support to endothelial cells by DM2-CSCs. In conclusion, DM2 and MetS worsen microenvironmental conditioning by CSCs. Appropriate modulation of autophagy and OxSt in human CSCs appears to restore these features, mostly in DM2-CSCs, suggesting a novel strategy against cardiac fibrosis in dysmetabolic patients. This article is protected by copyright. All rights reserved.

Progressive stages of dysmetabolism are associated with impaired biological features of human cardiac stromal cells mediated by the oxidative state and autophagy / Pagano, Francesca; Picchio, Vittorio; Bordin, Antonella; Cavarretta, Elena; Nocella, Cristina; Cozzolino, Claudia; Floris, Erica; Angelini, Francesco; Sordano, Alessia; Peruzzi, Mariangela; Miraldi, Fabio; Biondi-Zoccai, Giuseppe; De Falco, Elena; Carnevale, Roberto; Sciarretta, Sebastiano; Frati, Giacomo; Chimenti, Isotta. - In: JOURNAL OF PATHOLOGY. - ISSN 0022-3417. - 258:2(2022), pp. 136-148. [10.1002/path.5985]

Progressive stages of dysmetabolism are associated with impaired biological features of human cardiac stromal cells mediated by the oxidative state and autophagy

Picchio, Vittorio;Bordin, Antonella;Cavarretta, Elena;Nocella, Cristina;Cozzolino, Claudia;Floris, Erica;Angelini, Francesco;Peruzzi, Mariangela;Miraldi, Fabio;Biondi-Zoccai, Giuseppe;De Falco, Elena;Carnevale, Roberto;Sciarretta, Sebastiano;Frati, Giacomo;Chimenti, Isotta
Ultimo
2022

Abstract

: Cardiac stromal cells (CSCs) are the main players in fibrosis. Dysmetabolic conditions (metabolic syndrome - MetS, and type 2 diabetes - DM2) are strong pathogenetic contributors to cardiac fibrosis. Moreover, modulation of the oxidative state (OxSt) and autophagy is a fundamental function affecting the fibrotic commitment of CSCs, that are adversely modulated in MetS/DM2. We aimed to characterize CSCs from dysmetabolic patients, and to obtain a beneficial phenotypic setback from such fibrotic commitment by modulation of OxSt and autophagy. CSCs were isolated from 38 patients, stratified as MetS, DM2, or controls. Pharmacological modulation of OxSt and autophagy was obtained by treatment with trehalose and NOX4/NOX5 inhibitors (TREiNOX). Flow-cytometry and RT-qPCR analyses showed significantly increased expression of myofibroblasts markers in MetS-CSCs at baseline (GATA4, ACTA2, THY1/CD90) and after starvation (COL1A1, COL3A1). MetS- and DM2-CSCs displayed a paracrine profile distinct from control cells, as evidenced by heatmap analysis of 30 secreted cytokines, with significant reduction in VEGF and endoglin confirmed by ELISA. DM2-CSCs showed significantly reduced support to endothelial cells in angiogenic assays, and significantly increased H2 O2 release and NOX4/5 expression levels. Autophagy impairment after starvation (reduced ATG7 and LC3-II proteins) was also detectable in DM2-CSCs. TREiNOX treatment significantly reduced ACTA2, COL1A1, COL3A1, and NOX4 expression in both DM2- and MetS-CSCs, as well as GATA4 and THY1/CD90 in DM2, all versus control cells. Moreover, TREiNOX significantly increased VEGF release by DM2-CSCs, and VEGF and endoglin release by both MetS- and DM2-CSCs, also recovering the angiogenic support to endothelial cells by DM2-CSCs. In conclusion, DM2 and MetS worsen microenvironmental conditioning by CSCs. Appropriate modulation of autophagy and OxSt in human CSCs appears to restore these features, mostly in DM2-CSCs, suggesting a novel strategy against cardiac fibrosis in dysmetabolic patients. This article is protected by copyright. All rights reserved.
2022
cardiac stromal cells; anti-fibrotic therapy; autophagy; cardiac fibroblasts; cardiac fibrosis; metabolic syndrome; oxidative stress; type 2 diabetes
01 Pubblicazione su rivista::01a Articolo in rivista
Progressive stages of dysmetabolism are associated with impaired biological features of human cardiac stromal cells mediated by the oxidative state and autophagy / Pagano, Francesca; Picchio, Vittorio; Bordin, Antonella; Cavarretta, Elena; Nocella, Cristina; Cozzolino, Claudia; Floris, Erica; Angelini, Francesco; Sordano, Alessia; Peruzzi, Mariangela; Miraldi, Fabio; Biondi-Zoccai, Giuseppe; De Falco, Elena; Carnevale, Roberto; Sciarretta, Sebastiano; Frati, Giacomo; Chimenti, Isotta. - In: JOURNAL OF PATHOLOGY. - ISSN 0022-3417. - 258:2(2022), pp. 136-148. [10.1002/path.5985]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1649645
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