ArticleCirculation2013
A crucial role for p90RSK-mediated reduction of ERK5 transcriptional activity in endothelial dysfunction and atherosclerosis.
Article in Circulation, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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Who cites it
79 citing papers in PubMed, 113 citations in OpenAlex.
- Senescent Phenotype Induced by p90RSK-NRF2 Signaling Sensitizes Monocytes and Macrophages to Oxidative Stress in HIV-Positive Individuals.Circulation · 2019Trial
- LATS1/2-CD38 Metabolic Rewiring Links Senescence to Intraplaque Thrombosis.Circulation research · 2026Article
- RSK1-SRF signaling axis drives fibroblast activation and pulmonary fibrosis: Genetic causality and therapeutic targeting.iScience · 2026Article
- Erk5-mediated microglial ferroptosis drives ischemic white matter damage via the Nfatc4-Clptm1l axis.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Genetic crossroads of cardiovascular disease and its comorbidities: toward holistic therapeutic strategies.BMC medical genomics · 2025Article
- Impacts of Radiation on Metabolism and Vascular Cell Senescence.Antioxidants & redox signaling · 2025Review
- Mechanistic insights and emerging therapeutic strategies targeting endothelial dysfunction in cardiovascular diseases.Archives of pharmacal research · 2025Review
- TNIK-driven regulation of ERK5 transcriptional activity in endothelial cells.Frontiers in cardiovascular medicine · 2025Article
- Unravelling the Mechanisms of Oxidised Low-Density Lipoprotein in Cardiovascular Health: Current Evidence from In Vitro and In Vivo Studies.International journal of molecular sciences · 2024Review
- RSK1 and RSK2 as therapeutic targets: an up-to-date snapshot of emerging data.Expert opinion on therapeutic targets · 2024Review
- Mitogen-Activated Protein Kinases Mediate Adventitial Fibroblast Activation and Neointima Formation via GATA4/Cyclin D1 Axis.Cardiovascular drugs and therapy · 2024Article
- Potential diagnostic markers shared between non-alcoholic fatty liver disease and atherosclerosis determined by machine learning and bioinformatic analysis.Frontiers in medicine · 2024Article
- Aerobic Exercise Alters the Melanoma Microenvironment and Modulates ERK5 S496 Phosphorylation.Cancer immunology research · 2023Article
- An ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and Atherosclerosis.Circulation research · 2023Article
- Inhibition of p90RSK Ameliorates PDGF-BB-Mediated Phenotypic Change of Vascular Smooth Muscle Cell and Subsequent Hyperplasia of Neointima.International journal of molecular sciences · 2023Article
- Article
- Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition.Frontiers in cardiovascular medicine · 2023Article
- TNIK regulation of interferon signaling and endothelial cell response to virus infection.Frontiers in cardiovascular medicine · 2023Article
- Premature senescence and cardiovascular disease following cancer treatments: mechanistic insights.Frontiers in cardiovascular medicine · 2023Review
- The significance of ERK5 catalytic-independent functions in disease pathways.Frontiers in cell and developmental biology · 2023Review
19 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundDiabetes 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
resultsInducible 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.
conclusionsOur 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.