ArticleJournal of immunology (Baltimore, Md. : 1950)2014
Identification of activators of ERK5 transcriptional activity by high-throughput screening and the role of endothelial ERK5 in vasoprotective effects induced by statins and antimalarial agents.
Article in Journal of immunology (Baltimore, Md. : 1950), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 59 citations in OpenAlex.
- Reconceptualizing Endothelial-to-mesenchymal transition in atherosclerosis: Signaling pathways and prospective targeting strategies.Journal of advanced research · 2025Review
- Hydroxychloroquine improves manifestation of PE rats under oxidative stress by regulating the PI3K/AKT/mTOR signaling pathway to inhibit autophagy.Scientific reports · 2025Article
- TNIK-driven regulation of ERK5 transcriptional activity in endothelial cells.Frontiers in cardiovascular medicine · 2025Article
- Deciphering the immunological interactions: targeting preeclampsia with Hydroxychloroquine's biological mechanisms.Frontiers in pharmacology · 2024Review
- Endothelial mechanobiology in atherosclerosis.Cardiovascular research · 2023Review
- The Impact of Hydroxychloroquine on Primary Feto-Placental Endothelial Cells from Healthy and Early-Onset Preeclamptic Placentas.International journal of molecular sciences · 2023Article
- Effect of Hydroxychloroquine on Lupus Activity, Preeclampsia and Intrauterine Growth Restriction in Pregnant Women with Systemic Lupus Erythematosus and/or Antiphospholipid Syndrome: A Systematic Review and Meta-Analysis.Journal of clinical medicine · 2023Review
- 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
- Hydroxychloroquine Mitigates Dilated Cardiomyopathy Phenotype in Transgenic D94A Mice.International journal of molecular sciences · 2022Article
- Biologic Functions of Hydroxychloroquine in Disease: From COVID-19 to Cancer.Pharmaceutics · 2022Review
- Reciprocal regulation of endothelial-mesenchymal transition by MAPK7 and EZH2 in intimal hyperplasia and coronary artery disease.Scientific reports · 2021Article
- MEF2 (Myocyte Enhancer Factor 2) Is Essential for Endothelial Homeostasis and the Atheroprotective Gene Expression Program.Arteriosclerosis, thrombosis, and vascular biology · 2021Article
- Preventive Effects of Quercetin against the Onset of Atherosclerosis-Related Acute Aortic Syndromes in Mice.International journal of molecular sciences · 2020Article
- Article
- Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence.Journal of clinical medicine · 2020Review
- Hydroxychloroquine may be beneficial in preeclampsia and recurrent miscarriage.British journal of clinical pharmacology · 2020Review
- Article
- Network-based approach to prediction and population-based validation of in silico drug repurposing.Nature communications · 2018Article
- Article
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
Abstract
Because ERK5 inhibits endothelial inflammation and dysfunction, activating ERK5 might be a novel approach to protecting vascular endothelial cells (ECs) against various pathological conditions of the blood vessel. We have identified small molecules that protect ECs via ERK5 activation and determined their contribution to preventing cardiac allograft rejection. Using high-throughput screening, we identified certain statins and antimalarial agents including chloroquine, hydroxychloroquine, and quinacrine as strong ERK5 activators. Pitavastatin enhanced ERK5 transcriptional activity and Kruppel-like factor-2 expression in cultured human and bovine ECs, but these effects were abolished by the depletion of ERK5. Chloroquine and hydroxychloroquine upregulated ERK5 kinase activity and inhibited VCAM-1 expression in an ERK5-dependent but MAPK/ERK kinase 5- and Kruppel-like factor 2/4-independent manner. Leukocyte rolling and vascular reactivity were used to evaluate endothelial function in vivo, and we found that EC-specific ERK5 knockout (ERK5-EKO) mice exhibited increased leukocyte rolling and impaired vascular reactivity, which could not be corrected by pitavastatin. The role of endothelial ERK5 in acute cardiac allograft rejection was also examined by heterotopic grafting of the heart obtained from either wild-type or ERK5-EKO mice into allomismatched recipient mice. A robust increase in both inflammatory gene expression and CD45-positive cell infiltration into the graft was observed. These tissue rejection responses were inhibited by pitavastatin in wild-type but not ERK5-EKO hearts. Our study has identified statins and antimalarial drugs as strong ERK5 activators and shown that ERK5 activation is preventive of endothelial inflammation and dysfunction and acute allograft rejection.
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