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

Kyungsun Heo, Nhat Tu Le, Hannah J. Cushman, Carolyn J. Giancursio, Eugene Chang, Chang Hoon Woo, Mark A. Sullivan, Jack Taunton, Edward Yeh, Keigi Fujiwara, Jun-ichi Abe

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1299-1310
Number of pages12
JournalJournal of Clinical Investigation
Volume125
Issue number3
DOIs
StatePublished - Jan 1 2015

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SUMO-1 Protein
Atherosclerosis
Peptide Hydrolases
Phosphotransferases
Threonine
Endothelial Cells
Down-Regulation
Phosphorylation
Sumoylation
Cell Nucleus Active Transport
Protein-Serine-Threonine Kinases
Atherosclerotic Plaques
Aorta
Up-Regulation
Apoptosis
Lipids

ASJC Scopus subject areas

  • Medicine(all)

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Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function. / Heo, Kyungsun; Le, Nhat Tu; Cushman, Hannah J.; Giancursio, Carolyn J.; Chang, Eugene; Woo, Chang Hoon; Sullivan, Mark A.; Taunton, Jack; Yeh, Edward; Fujiwara, Keigi; Abe, Jun-ichi.

In: Journal of Clinical Investigation, Vol. 125, No. 3, 01.01.2015, p. 1299-1310.

Research output: Contribution to journalArticle

Heo, K, Le, NT, Cushman, HJ, Giancursio, CJ, Chang, E, Woo, CH, Sullivan, MA, Taunton, J, Yeh, E, Fujiwara, K & Abe, J 2015, 'Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function', Journal of Clinical Investigation, vol. 125, no. 3, pp. 1299-1310. https://doi.org/10.1172/JCI76453
Heo, Kyungsun ; Le, Nhat Tu ; Cushman, Hannah J. ; Giancursio, Carolyn J. ; Chang, Eugene ; Woo, Chang Hoon ; Sullivan, Mark A. ; Taunton, Jack ; Yeh, Edward ; Fujiwara, Keigi ; Abe, Jun-ichi. / Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 3. pp. 1299-1310.
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