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01-05-2021 | Propylthiouracil | Original Article

Inhibition of lysyl oxidase stimulates TGF-β signaling and metalloproteinases-2 and -9 expression and contributes to the disruption of ascending aorta in rats: protection by propylthiouracil

Authors: Valeria Merico, Jacopo Francesco Imberti, Mario Zanoni, Giuseppe Boriani, Silvia Garagna, Roberto Imberti

Published in: Heart and Vessels | Issue 5/2021

Abstract

Mutations in lysyl oxidase (LOX) genes cause severe vascular anomalies in mice and humans. LOX activity can be irreversibly inhibited by the administration of β-aminoproprionitrile (BAPN). We investigated the mechanisms underlying the damage to the ascending thoracic aorta induced by LOX deficiency and evaluated whether 6-propylthiouracil (PTU) can afford protection in rats. BAPN administration caused disruption of the ascending aortic wall, increased the number of apoptotic cells, stimulated TGF-β signaling (increase of nuclear p-SMAD2 staining), and up-regulated the expression of metalloproteinases-2 and -9. In BAPN-treated animals, PTU reduced apoptosis, p-SMAD2 staining, MMP-2, and -9 expression, and markedly decreased the damage to the aortic wall. Our results suggest that, as in some heritable vascular diseases, enhanced TGF-β signaling and upregulation of MMP-2 and -9 can contribute to the pathogenesis of ascending aorta damage caused by LOX deficiency. We have also shown that PTU, a drug already in clinical use, protects against the effects of LOX inhibition. MMP-2 and -9 might be potential targets of new therapeutic strategies for the treatment of vascular diseases caused by LOX deficiency.

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Title: Inhibition of lysyl oxidase stimulates TGF-β signaling and metalloproteinases-2 and -9 expression and contributes to the disruption of ascending aorta in rats: protection by propylthiouracil
Authors: Valeria Merico
Jacopo Francesco Imberti
Mario Zanoni
Giuseppe Boriani
Silvia Garagna
Roberto Imberti
Publication date: 01-05-2021
Publisher: Springer Japan
Keyword: Propylthiouracil
Published in: Heart and Vessels / Issue 5/2021
Print ISSN: 0910-8327
Electronic ISSN: 1615-2573
DOI: https://doi.org/10.1007/s00380-020-01750-6

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Inhibition of lysyl oxidase stimulates TGF-β signaling and metalloproteinases-2 and -9 expression and contributes to the disruption of ascending aorta in rats: protection by propylthiouracil

Abstract

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