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

Heart Vessels. 2021 May;36(5):738-747. doi: 10.1007/s00380-020-01750-6. Epub 2021 Jan 19.

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.

Keywords: Ascending aorta disruption; BAPN; Lysyl oxidase; Metalloproteinase-2 and -9; Propylthiouracil; TGF-β signaling.

MeSH terms

  • Animals
  • Antimetabolites / pharmacology
  • Aorta, Thoracic / metabolism*
  • Aortic Diseases / metabolism
  • Aortic Diseases / prevention & control*
  • Biomarkers / metabolism
  • Disease Models, Animal
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Male
  • Matrix Metalloproteinase 2 / biosynthesis*
  • Matrix Metalloproteinase 9 / biosynthesis*
  • Pilot Projects
  • Propylthiouracil / pharmacology*
  • Protein-Lysine 6-Oxidase / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Transforming Growth Factor beta / metabolism*

Substances

  • Antimetabolites
  • Biomarkers
  • Transforming Growth Factor beta
  • Propylthiouracil
  • Protein-Lysine 6-Oxidase
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9