NAD + repletion inhibits the endothelial-to-mesenchymal transition induced by TGF-β in endothelial cells through improving mitochondrial unfolded protein response

Int J Biochem Cell Biol. 2019 Dec;117:105635. doi: 10.1016/j.biocel.2019.105635. Epub 2019 Oct 15.


Endothelial-to-mesenchymal transition (EndMT) plays an important role in the progression of cardiac fibrosis but its mechanism and treatment need to be further understood. Herein, we have found that mitochondrial unfolded protein response (mtUPR) played a critical role in transforming growth factor beta 1 (TGF-β1)-induced EndMT in endothelial cells (ECs). MtUPR was repressed in endothelial cells after exposure to TGF-β1. NAD + precursor nicotinamide riboside (NR) could attenuate TGF-β1-induced EndMT and improve the levels of mtUPR. Significantly, prohibitin proteins (PHB and PHB2) was also regulated by nicotinamide riboside. Moreover, we found that inhibition of prohibitin proteins could prevent the protective effect of nicotinamide riboside on mtUPR and TGF-β1-induced EndMT. Overexpression of prohibitin proteins could alleviate mitochondrial function and TGF-β1-induced EndMT through improving mtUPR. In vivo, The EndMT of ECs induced by Transverse aortic constriction (TAC) in mouse was inhibited by NR. In conclusion, our results indicate that nicotinamide riboside improved the expression of prohibitin proteins to ameliorate EndMT via promotion of mtUPR. Nicotinamide riboside is a potential therapeutic target for cardiac fibrosis.

Keywords: Endothelial cells; Endothelial-mesenchymal transition; Mitochondrial unfolded protein response; Nicotinamide riboside; Prohibitin proteins.

MeSH terms

  • Animals
  • Endothelial Cells / metabolism*
  • Epithelial-Mesenchymal Transition / physiology*
  • Humans
  • Male
  • Mice
  • NAD / metabolism*
  • Prohibitins
  • Transfection
  • Transforming Growth Factor beta / metabolism*
  • Unfolded Protein Response


  • PHB protein, human
  • PHB2 protein, human
  • Phb2 protein, mouse
  • Prohibitins
  • Transforming Growth Factor beta
  • NAD