A Crucial Role for p90RSK-Mediated Reduction of ERK5 Transcriptional Activity in Endothelial Dysfunction and Atherosclerosis

Title
A Crucial Role for p90RSK-Mediated Reduction of ERK5 Transcriptional Activity in Endothelial Dysfunction and Atherosclerosis
Author(s)
Nhat-Tu Le[Nhat-Tu Le]Kyung-Sun Heo[Kyung-Sun Heo]Yuichiro Takei[Yuichiro Takei]Hakjoo Lee[Hakjoo Lee]우창훈Eugene Chang[Eugene Chang]Carolyn McClain[Carolyn McClain]Cheryl Hurley[Cheryl Hurley]Xin Wang[Xin Wang]Faqian Li[Faqian Li]Haodong Xu[Haodong Xu]Craig Morrell[Craig Morrell]Mark Sullivan[Mark Sullivan]Michael Cohen[Michael Cohen]Iana Serafimova[Iana Serafimova]Jack Taunton[Jack Taunton]Keigi Fujiwara[Keigi Fujiwara]Jun-ichi Abe[Jun-ichi Abe]
Keywords
ACTIVATED PROTEIN-KINASE; RIBOSOMAL S6 KINASE; SIGNAL-REGULATED KINASE-5; E-DEFICIENT MICE; SHEAR-STRESS; TARGETED DELETION; LESION FORMATION; P90 RSK; CELLS; EXPRESSION
Issue Date
201301
Publisher
LIPPINCOTT WILLIAMS & WILKINS
Citation
CIRCULATION, v.127, no.4, pp.486 - +
Abstract
Background-Diabetes mellitus is a major risk factor for cardiovascular mortality by increasing endothelial cell (EC) dysfunction and subsequently accelerating atherosclerosis. Extracellular-signal regulated kinase 5 (ERK5) is activated by steady laminar flow and regulates EC function by increasing endothelial nitric oxide synthase expression and inhibiting EC inflammation. However, the role and regulatory mechanisms of ERK5 in EC dysfunction and atherosclerosis are poorly understood. Here, we report the critical role of the p90 ribosomal S6 kinase (p90RSK)/ERK5 complex in EC dysfunction in diabetes mellitus and atherosclerosis. Methods and Results-Inducible EC-specific ERK5 knockout (ERK5-EKO) mice showed increased leukocyte rolling and impaired vessel reactivity. To examine the role of endothelial ERK5 in atherosclerosis, we used inducible ERK5-EKO-LDLR-/- mice and observed increased plaque formation. When activated, p90RSK associated with ERK5, and this association inhibited ERK5 transcriptional activity and upregulated vascular cell adhesion molecule 1 expression. In addition, p90RSK directly phosphorylated ERK5 S496 and reduced endothelial nitric oxide synthase expression. p90RSK activity was increased in diabetic mouse vessels, and fluoromethyl ketone-methoxyethylamine, a specific p90RSK inhibitor, ameliorated EC-leukocyte recruitment and diminished vascular reactivity in diabetic mice. Interestingly, in ERK5-EKO mice, increased leukocyte rolling and impaired vessel reactivity were resistant to the beneficial effects of fluoromethyl ketone-methoxyethylamine, suggesting a critical role for endothelial ERK5 in mediating the salutary effects of fluoromethyl ketone-methoxyethylamine on endothelial dysfunction. Fluoromethyl ketone-methoxyethylamine also inhibited atherosclerosis formation in ApoE(-/-) mice. Conclusions-Our study highlights the importance of the p90RSK/ERK5 module as a critical mediator of EC dysfunction in diabetes mellitus and atherosclerosis formation, thus revealing a potential new target for therapeutic intervention. (Circulation. 2013;127:486-499.)
URI
http://hdl.handle.net/YU.REPOSITORY/26839http://dx.doi.org/10.1161/CIRCULATIONAHA.112.116988
ISSN
0009-7322
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의과대학 > 약리학교실 > Articles
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