University of Massachusetts Medical School Faculty Publications
Title
Neural JNK3 regulates blood flow recovery after hindlimb ischemia in mice via an Egr1/Creb1 axis
UMMS Affiliation
Division of Cardiovascular Medicine, Department of Medicine; Program in Molecular Medicine; Department of Neurobiology; Freeman Lab; Davis Lab
Publication Date
2019-09-17
Document Type
Article
Disciplines
Cardiovascular Diseases | Cellular and Molecular Physiology | Enzymes and Coenzymes | Nervous System | Neuroscience and Neurobiology
Abstract
Diseases related to impaired blood flow such as peripheral artery disease (PAD) impact nearly 10 million people in the United States alone, yet patients with clinical manifestations of PAD (e.g., claudication and limb ischemia) have limited treatment options. In ischemic tissues, stress kinases such as c-Jun N-terminal kinases (JNKs), are activated. Here, we show that inhibition of the JNK3 (Mapk10) in the neural compartment strikingly potentiates blood flow recovery from mouse hindlimb ischemia. JNK3 deficiency leads to upregulation of growth factors such as Vegfa, Pdgfb, Pgf, Hbegf and Tgfb3 in ischemic muscle by activation of the transcription factors Egr1/Creb1. JNK3 acts through Forkhead box O3 (Foxo3a) to suppress the activity of Egr1/Creb1 transcription regulators in vitro. In JNK3-deficient cells, Foxo3a is suppressed which leads to Egr1/Creb1 activation and upregulation of downstream growth factors. Collectively, these data suggest that the JNK3-Foxo3a-Egr1/Creb1 axis coordinates the vascular remodeling response in peripheral ischemia.
Keywords
Mechanisms of disease, Peripheral vascular disease
Rights and Permissions
Copyright © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
10.1038/s41467-019-11982-4
Source
Nat Commun. 2019 Sep 17;10(1):4223. doi: 10.1038/s41467-019-11982-4. Link to article on publisher's site
Related Resources
Journal/Book/Conference Title
Nature communications
PubMed ID
31530804
Repository Citation
Kant S, Craige SM, Chen K, Reif MM, Learnard H, Kelly M, Caliz AD, Tran KT, Ramo K, Peters OM, Freeman MR, Davis RJ, Keaney JF. (2019). Neural JNK3 regulates blood flow recovery after hindlimb ischemia in mice via an Egr1/Creb1 axis. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1038/s41467-019-11982-4. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1640
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Cardiovascular Diseases Commons, Cellular and Molecular Physiology Commons, Enzymes and Coenzymes Commons, Nervous System Commons, Neuroscience and Neurobiology Commons