Inhibition of enzymes involved in collagen cross-linking reduces vascular smooth muscle cell calcification

Eva Jover, Ana Silvente, Francisco Marín, José Martínez-González, Mar Orriols, Carlos M. Martinez, Carmen María Puche, Mariano Valdés, Cristina Rodriguez, Diana Hernández-Romero*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

22 Citations (Scopus)

Abstract

Vascular smooth muscle cells (VSMCs) transdifferentiate into osteoblast-like cells during vascular calcification, inducing active remodeling and calcification of the extracellular matrix (ECM). Intracellular and extracellular enzymes, such as lysyl hydroxylase 1 (PLOD1) and lysyl oxidase (LOX), contribute to ECM maturation and stabilization. We assessed the contribution of these enzymes to hyperphosphatemia-induced calcification. Human and murine VSMCs were differentiated into functional osteoblast-like cells by high-phosphate medium (HPM) conditioning. HPM promoted ECM calcification and up-regulated osteoblast markers associated with induction of LOX and PLOD1 expression and with an increase in ECM-insoluble collagen deposition. Murine VSMCs from transgenic mice overexpressing LOX (TgLOX) exhibited an increase in HPM-dependent calcification and osteoblast commitment compared with wild-type cells. Similarly, enhanced HPM-induced calcification was detected in aorta from TgLOX. Conversely, b-aminopropionitrile (a LOX inhibitor) and LOX knockdown abrogated VSMC calcification and transdifferentiation. We found a significant positive association between LOX expression and vascular calcification in human atherosclerotic lesions. Likewise, 2,29-dipyridil (a PLOD inhibitor) and PLOD1 knockdown impaired HPM-induced ECM mineralization and osteoblast commitment. Our findings identify LOX and PLOD as critical players in vascular calcification and highlight the importance of ECM remodeling in this process.

Original languageEnglish
Pages (from-to)4459-4469
Number of pages11
JournalFASEB Journal
Volume32
Issue number8
Early online date30 Jul 2018
DOIs
Publication statusPublished - 1 Aug 2018

Keywords

  • BAPN
  • Dipyridyl
  • Extracellular matrix
  • LOX
  • PLOD1

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