NEDDylation promotes endothelial dysfunction: A role for HDAC2

Deepesh Pandey, Daijiro Hori, Jae Hyung Kim, Yehudit Bergman, Dan E. Berkowitz, Lewis H. Romer

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Emerging evidence strongly supports a role for HDAC2 in the transcriptional regulation of endothelial genes and vascular function. We have recently demonstrated that HDAC2 reciprocally regulates the transcription of Arginase2, which is itself a critical modulator of endothelial function via eNOS. Moreover HDAC2 levels are decreased in response to the atherogenic stimulus OxLDL via a mechanism that is apparently dependent upon proteasomal degradation. NEDDylation is a post-translational protein modification that is tightly linked to ubiquitination and thereby protein degradation. We propose that changes in NEDDylation may modulate vascular endothelial function in part through alterations in the proteasomal degradation of HDAC2. In HAEC, OxLDL exposure augmented global protein NEDDylation. Pre-incubation of mouse aortic rings with the NEDDylation activating enzyme inhibitor, MLN4924, prevented OxLDL-induced endothelial dysfunction. In HAEC, MLN enhanced HDAC2 abundance, decreased expression and activity of Arginase2, and blocked OxLDL-mediated reduction of HDAC2. Additionally, HDAC2 was shown to be a substrate for NEDD8 conjugation and this interaction was potentiated by OxLDL. Further, HDAC2 levels were reciprocally regulated by ectopic expression of NEDD8 and the de-NEDDylating enzyme SENP8. Our findings indicate that the observed improvement in endothelial dysfunction with inhibition of NEDDylation activating enzyme is likely due to an HDAC2-dependent decrease in Arginase2. NEDDylation activating enzyme may therefore be a novel target in endothelial dysfunction and atherogenesis.

Original languageEnglish (US)
Pages (from-to)18-22
Number of pages5
JournalJournal of molecular and cellular cardiology
StatePublished - Apr 1 2015
Externally publishedYes


  • Atherosclerosis
  • Endothelial dysfunction
  • NEDDylation
  • Protein degradation
  • Ubiquitination
  • Vascular endothelium

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine


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