TY - JOUR
T1 - Inhibition of lysyl oxidase stimulates TGF-β signaling and metalloproteinases-2 and -9 expression and contributes to the disruption of ascending aorta in rats
T2 - protection by propylthiouracil
AU - Merico, Valeria
AU - Imberti, Jacopo Francesco
AU - Zanoni, Mario
AU - Boriani, Giuseppe
AU - Garagna, Silvia
AU - Imberti, Roberto
N1 - Funding Information:
This study was supported by Fondazione IRCCS Policlinico San Matteo, Pavia and the Italian Ministry of Education, University and Research (MIUR): Dipartimenti di Eccellenza Programme (2018–2022)—Department of Biology and Biotechnology.
Publisher Copyright:
© 2021, Springer Japan KK, part of Springer Nature.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Ascending aorta disruption
KW - BAPN
KW - Lysyl oxidase
KW - Metalloproteinase-2 and -9
KW - Propylthiouracil
KW - TGF-β signaling
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U2 - 10.1007/s00380-020-01750-6
DO - 10.1007/s00380-020-01750-6
M3 - Article
C2 - 33462684
AN - SCOPUS:85100081298
JO - Heart and Vessels
JF - Heart and Vessels
SN - 0910-8327
ER -