A crucial role for p90RSK-mediated reduction of ERK5 transcriptional activity in endothelial dysfunction and atherosclerosis.

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.

• Authors: Nhat-Tu Le, Kyung-Sun Heo, Yuichiro Takei, Hakjoo Lee, Chang-Hoon Woo, Eugene Chang, Carolyn McClain, Cheryl Hurley, Xin Wang, Faqian Li, Haodong Xu, Craig Morrell, Mark A Sullivan, Michael S Cohen, Iana M Serafimova, Jack Taunton, Keigi Fujiwara, Jun-Ichi Abe
• Journal: Circulation (Circulation) Vol. 127 Issue 4 Pg. 486-99 (Jan 29 2013) ISSN: 1524-4539 [Electronic] United States
• PMID: 23243209 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Chloromethyl Ketones
• Oxidants
• Hydrogen Peroxide
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• Ribosomal Protein S6 Kinases, 90-kDa
• Rps6ka1 protein, mouse
• Mitogen-Activated Protein Kinase 7
• Glucose

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Animals
• Atherosclerosis (drug therapy, metabolism, physiopathology)
• Diabetic Angiopathies (drug therapy, metabolism, physiopathology)
• Drug Synergism
• Glucose (pharmacology)
• Human Umbilical Vein Endothelial Cells
• Humans
• Hydrogen Peroxide (pharmacology)
• Leukocyte Rolling (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Mutant Strains
• Mitogen-Activated Protein Kinase 7 (genetics, metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Oxidants (pharmacology)
• Phosphorylation (physiology)
• Rats
• Ribosomal Protein S6 Kinases, 90-kDa (antagonists & inhibitors, genetics, metabolism)