Lack of periostin leads to suppression of Notch1 signaling and calcific aortic valve disease

Tatiana V. Tkatchenko, Ricardo A. Moreno-Rodriguez, Simon J. Conway, Jeffery D. Molkentin, Roger R. Markwald, Andrei V. Tkatchenko

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

The Postn gene encodes protein periostin. During embryonic development, it is highly expressed in the outflow tract (OFT) endocardial cushions of the developing heart, which give rise to several structures of the mature heart including the aortic valve. Periostin was previously implicated in osteoblast differentiation, cancer metastasis, and tooth and bone development, but its role in cardiac OFT development is unclear. To elucidate the role that periostin plays in the developing heart we analyzed cardiac OFT phenotype in mice after deletion of the Postn gene. We found that lack of periostin in the embryonic OFT leads to ectopic expression of the proosteogenic growth factor pleiotrophin (Ptn) and overexpression of delta-like 1 homolog (Dlk1), a negative regulator of Notch1, in the distal (prevalvular) cushions of the OFT. This resulted in suppression of Notch1 signaling, strong induction of the central transcriptional regulator of osteoblast cell fate Runx2, upregulation of osteopontin and osteocalcin expression, and subsequent calcification of the aortic valve. Our data suggest that periostin represses a default osteogenic program in the OFT cushion mesenchyme and promotes differentiation along a fibrogenic lineage. Lack of periostin causes derepression of the osteogenic potential of OFT mesenchymal cells, calcium deposition, and calcific aortic valve disease. These results establish periostin as a key regulator of OFT endocardial cushion mesenchymal cell fate during embryonic development.

Original languageEnglish (US)
Pages (from-to)160-168
Number of pages9
JournalPhysiological Genomics
Volume39
Issue number3
DOIs
StatePublished - Nov 1 2009

Keywords

  • Development
  • Endocardial cushions
  • Outflow tract

ASJC Scopus subject areas

  • Physiology
  • Genetics

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    Tkatchenko, T. V., Moreno-Rodriguez, R. A., Conway, S. J., Molkentin, J. D., Markwald, R. R., & Tkatchenko, A. V. (2009). Lack of periostin leads to suppression of Notch1 signaling and calcific aortic valve disease. Physiological Genomics, 39(3), 160-168. https://doi.org/10.1152/physiolgenomics.00078.2009