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

• Published in: Circulation (New York, N.Y.) Vol. 127; no. 4; pp. 486 - 499
• Main Authors: LE, Nhat-Tu, HEO, Kyung-Sun, HAODONG XU, MORRELL, Craig, SULLIVAN, Mark A, COHEN, Michael S, SERAFIMOVA, Iana M, TAUNTON, Jack, FUJIWARA, Keigi, ABE, Jun-Ichi, TAKEI, Yuichiro, LEE, Hakjoo, WOO, Chang-Hoon, CHANG, Eugene, MCCLAIN, Carolyn, HURLEY, Cheryl, XIN WANG, FAQIAN LI
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 29-01-2013
• Subjects: Amino Acid Chloromethyl Ketones - pharmacology; Animals; Atherosclerosis (general aspects, experimental research); Atherosclerosis - drug therapy; Atherosclerosis - metabolism; Atherosclerosis - physiopathology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Diabetic Angiopathies - drug therapy; Diabetic Angiopathies - metabolism; Diabetic Angiopathies - physiopathology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Drug Synergism; Glucose - pharmacology; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen Peroxide - pharmacology; Leukocyte Rolling - physiology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Mitogen-Activated Protein Kinase 7 - genetics; Mitogen-Activated Protein Kinase 7 - metabolism; Nitric Oxide Synthase Type III - metabolism; Oxidants - pharmacology; Phosphorylation - physiology; Rats; Ribosomal Protein S6 Kinases, 90-kDa - antagonists & inhibitors; Ribosomal Protein S6 Kinases, 90-kDa - genetics; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; Endocrinopathy; Vascular disease; Signal transduction; Diabetes mellitus; Atherosclerosis; ERK5; Endothelial dysfunction; Cardiovascular disease; p90RSK
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.112.116988

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.
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.
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.