Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function

J Clin Invest. 2015 Mar 2;125(3):1299-310. doi: 10.1172/JCI76453. Epub 2015 Feb 17.


Disturbed blood flow (d-flow) causes endothelial cell (EC) dysfunction, leading to atherosclerotic plaque formation. We have previously shown that d-flow increases SUMOylation of p53 and ERK5 through downregulation of sentrin/SUMO-specific protease 2 (SENP2) function; however, it is not known how SENP2 itself is regulated by d-flow. Here, we determined that d-flow activated the serine/threonine kinase p90RSK, which subsequently phosphorylated threonine 368 (T368) of SENP2. T368 phosphorylation promoted nuclear export of SENP2, leading to downregulation of eNOS expression and upregulation of proinflammatory adhesion molecule expression and apoptosis. In an LDLR-deficient murine model of atherosclerosis, EC-specific overexpression of p90RSK increased EC dysfunction and lipid accumulation in the aorta compared with control animals; however, these pathologic changes were not observed in atherosclerotic mice overexpressing dominant negative p90RSK (DN-p90RSK). Moreover, depletion of SENP2 in these mice abolished the protective effect of DN-p90RSK overexpression. We propose that p90RSK-mediated SENP2-T368 phosphorylation is a master switch in d-flow-induced signaling, leading to EC dysfunction and atherosclerosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Apoptosis
  • Atherosclerosis / enzymology*
  • Atherosclerosis / physiopathology
  • Carotid Arteries / enzymology
  • Carotid Arteries / pathology
  • Cells, Cultured
  • Cysteine Endopeptidases / physiology*
  • Enzyme Activation
  • Female
  • Human Umbilical Vein Endothelial Cells / physiology*
  • Humans
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 7 / metabolism
  • Phosphorylation
  • Plaque, Atherosclerotic / enzymology
  • Regional Blood Flow
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Sumoylation*
  • Tumor Suppressor Protein p53 / metabolism
  • Vasculitis / enzymology


  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Mitogen-Activated Protein Kinase 7
  • Cysteine Endopeptidases
  • SENP2 protein, human