title: NEDDylation promotes endothelial dysfunction: a role for HDAC2.
abstract: 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.
authors: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4904, USA.
authors: Deepesh
authors: D
authors: Pandey
authors: Department of Surgery, Division of Cardiac Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4904, USA.
authors: Daijiro
authors: D
authors: Hori
authors: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4904, USA.
authors: Jae Hyung
authors: JH
authors: Kim
authors: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4904, USA.
authors: Yehudit
authors: Y
authors: Bergman
authors: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4904, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4904, USA.
authors: Dan E
authors: DE
authors: Berkowitz
authors: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4904, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4904, USA; Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4904, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4904, USA; Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4904, USA. Electronic address: LRomer@jhmi.edu.
authors: Lewis H
authors: LH
authors: Romer
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D003517:Cyclopentanes / Q000494:pharmacology; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056464:Histone Deacetylase 2 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology; D051379:Mice; D000075687:NEDD8 Protein; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D059748:Proteolysis / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D054875:Ubiquitination; D014452:Ubiquitins / Q000235:genetics* / Q000378:metabolism
chemical_list: D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; D014452:Ubiquitins; C099252:oxidized low density lipoprotein; D010450:Endopeptidases; C477008:SENP8 protein, human; D046988:Proteasome Endopeptidase Complex; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2; C477631:ARG2 protein, human; D001119:Arginase; C539933:pevonedistat
keywords: Atherosclerosis; Endothelial dysfunction; NEDDylation; Protein degradation; Ubiquitination; Vascular endothelium