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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalHeart and Vessels
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • Ascending aorta disruption
  • BAPN
  • Lysyl oxidase
  • Metalloproteinase-2 and -9
  • Propylthiouracil
  • TGF-β signaling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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