Extracellular signal-regulated kinase 5 SUMOylation antagonizes shear stress-induced antiinflammatory response and endothelial nitric oxide synthase expression in endothelial cells

Chang Hoon Woo, Tetsuro Shishido, Carolyn McClain, Jae Hyang Lim, Jian Dong Li, Jay Yang, Chen Yan, Jun-ichi Abe

Research output: Contribution to journalArticle

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Abstract

Shear stress-induced extracellular signal-regulated kinase (ERK)5 activation and the consequent regulation of Kruppel-like factor 2 and endothelial nitric oxide synthase expression represents one of the antiinflammatory and vascular tone regulatory mechanisms maintaining normal endothelial function. Endothelial dysfunction is a major initiator of atherosclerosis, a vascular pathology often associated with diabetes. Small ubiquitin-like modifier (SUMO) covalently attaches to certain residues of specific target transcription factors and could inhibit its activity. We investigated whether H2O2 and AGE (advanced glycation end products), 2 well-known mediators of diabetes, negatively regulated ERK5 transcriptional activity and laminar flow-induced endothelial nitric oxide synthase expression through ERK5 SUMOylation. H2O2 and AGE induced endogenous ERK5 SUMOylation. In addition, ERK5 SUMOylation was increased in the aortas from diabetic mice. ERK5 transcriptional activity, but not kinase activity, was inhibited by expression of Ubc9 (SUMO E2 conjugase) or PIAS1 (E3 ligase), suggesting the involvement of ERK5 SUMOylation on its transcriptional activity. Point-mutation analyses showed that ERK5 is covalently modified by SUMO at 2 conserved sites, Lys6 and Lys22, and that the SUMOylation defective mutant of ERK5, dominant negative form of Ubc9 (DN-Ubc9), and small interfering RNA PIAS1 reversed H2O2 and AGE-mediated reduction of shear stress-mediated ERK5/myocyte enhancer factor 2 transcriptional activity, as well as promoter activity of Kruppel-like factor 2. Finally, PIAS1 knockdown reversed the inhibitory effect of H2O2 in shear stress-induced Kruppel-like factor 2 and endothelial nitric oxide synthase expression. These data clearly defined SUMOylation-dependent ERK5 transcriptional repression independent of kinase activity and suggested this process as among the molecular mechanisms of diabetes-mediated endothelial dysfunction.

Original languageEnglish (US)
Pages (from-to)538-545
Number of pages8
JournalCirculation Research
Volume102
Issue number5
DOIs
StatePublished - Mar 1 2008

Fingerprint

Mitogen-Activated Protein Kinase 7
Sumoylation
Nitric Oxide Synthase Type III
Anti-Inflammatory Agents
Endothelial Cells
Kruppel-Like Transcription Factors
Advanced Glycosylation End Products
Ubiquitin
Blood Vessels
Phosphotransferases
gamma-Glutamyl Hydrolase
MEF2 Transcription Factors
Ubiquitin-Protein Ligases
Point Mutation
Small Interfering RNA
Aorta
Atherosclerosis
Transcription Factors
Pathology

Keywords

  • Diabetes
  • ERK5
  • KLF2
  • SUMOylation
  • Shear stress

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Extracellular signal-regulated kinase 5 SUMOylation antagonizes shear stress-induced antiinflammatory response and endothelial nitric oxide synthase expression in endothelial cells. / Woo, Chang Hoon; Shishido, Tetsuro; McClain, Carolyn; Lim, Jae Hyang; Li, Jian Dong; Yang, Jay; Yan, Chen; Abe, Jun-ichi.

In: Circulation Research, Vol. 102, No. 5, 01.03.2008, p. 538-545.

Research output: Contribution to journalArticle

Woo, Chang Hoon ; Shishido, Tetsuro ; McClain, Carolyn ; Lim, Jae Hyang ; Li, Jian Dong ; Yang, Jay ; Yan, Chen ; Abe, Jun-ichi. / Extracellular signal-regulated kinase 5 SUMOylation antagonizes shear stress-induced antiinflammatory response and endothelial nitric oxide synthase expression in endothelial cells. In: Circulation Research. 2008 ; Vol. 102, No. 5. pp. 538-545.
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AU - Yan, Chen

AU - Abe, Jun-ichi

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