Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function
Kyung-Sun Heo, … , Keigi Fujiwara, Jun-ichi Abe
Kyung-Sun Heo, … , Keigi Fujiwara, Jun-ichi Abe
Published February 17, 2015
Citation Information: J Clin Invest. 2015;125(3):1299-1310. https://doi.org/10.1172/JCI76453.
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Research Article Vascular biology

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

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.

Authors

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

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Figure 1

Role of p90RSK activation in d-flow–induced apoptosis and inflammation.

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Role of p90RSK activation in d-flow–induced apoptosis and inflammation. ...
(A–C) HUVECs were stimulated by d-flow (upper panel) or s-flow (lower panel) for indicated times, and p90RSK (A) and ERK5 (B) activation were examined by Western blotting using anti–phospho-p90RSK and anti–phospho-ERK5 (T218/Y220), respectively. (C) Quantification of d-flow–induced p90RSK and ERK5 activation is shown after normalization by total protein levels. Data represent mean ± SEM (0 minutes = 100, n = 3). (D) HUVECs were transduced with 50 MOI of Ad-LacZ, Ad-WT-p90RSK, or Ad-DN-p90RSK for 18 hours and then stimulated by d-flow or no flow for 36 hours, followed by TUNEL staining. Images were recorded as described in Methods after counterstaining with DAPI to visualize nuclei. Apoptotic nuclei are indicated by arrows (left panel). Quantification of apoptosis is shown as the percentage of TUNEL-positive cells (right panel). Data represent mean ± SEM, n = 5. Scale bars: 60 μm. (E and F) HUVECs were transduced with 50 MOI of Ad-LacZ, Ad-WT-p90RSK, or Ad-DN-p90RSK and then stimulated by d-flow for 24 hours. Expression of cleaved caspase-3 (E) or E-selectin, ICAM-1, VCAM-1, p90RSK, and tubulin (F) is shown. *P < 0.05; **P < 0.01, by 1-way ANOVA followed by Bonferroni’s post hoc test.