Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function
The Journal of Clinical Investigation
|February 18, 2015
Summary
Disturbed blood flow activates p90RSK, which phosphorylates SENP2, promoting endothelial cell dysfunction and atherosclerosis. This signaling pathway is crucial for the development of atherosclerotic plaques.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Pathophysiology
Background:
- Disturbed blood flow (d-flow) is a known cause of endothelial cell (EC) dysfunction and atherosclerotic plaque formation.
- Previous studies indicated d-flow increases SUMOylation of p53 and ERK5 by downregulating sentrin/SUMO-specific protease 2 (SENP2).
- The precise regulation of SENP2 by d-flow remained unclear.
Purpose of the Study:
- To elucidate the mechanism by which disturbed blood flow regulates SENP2.
- To investigate the role of p90RSK in SENP2 regulation and its downstream effects on ECs.
- To determine the therapeutic potential of targeting this pathway in atherosclerosis.
Main Methods:
- Investigated the effect of d-flow on SENP2 phosphorylation using cell culture models.
- Utilized Western blotting and immunofluorescence to assess protein localization and expression.
- Employed a low-density lipoprotein receptor-deficient (LDLR-/-) murine model of atherosclerosis to study in vivo effects.
- Generated EC-specific overexpression and dominant-negative p90RSK mouse models.
- Performed SENP2 depletion studies in vivo.
Main Results:
- Disturbed blood flow activated p90RSK, which phosphorylated SENP2 at Threonine 368 (T368).
- Phosphorylation at T368 induced nuclear export of SENP2, leading to reduced eNOS expression and increased expression of pro-inflammatory adhesion molecules and apoptosis.
- EC-specific overexpression of p90RSK in LDLR-/- mice exacerbated EC dysfunction and aortic lipid accumulation.
- Overexpression of dominant-negative p90RSK (DN-p90RSK) attenuated these pathological changes.
- Depletion of SENP2 abolished the protective effects of DN-p90RSK, highlighting SENP2's critical role.
Conclusions:
- p90RSK-mediated phosphorylation of SENP2 at T368 acts as a key regulator in response to disturbed blood flow.
- This signaling cascade promotes endothelial cell dysfunction and contributes to the pathogenesis of atherosclerosis.
- Targeting the p90RSK-SENP2 interaction may offer a novel therapeutic strategy for atherosclerosis.
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