Division of Cardiovascular Medicine, Department of Medicine; Program in Molecular Medicine; Department of Neurobiology; Freeman Lab; Davis Lab
Cardiovascular Diseases | Cellular and Molecular Physiology | Enzymes and Coenzymes | Nervous System | Neuroscience and Neurobiology
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.
Mechanisms of disease, Peripheral vascular disease
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DOI of Published Version
Nat Commun. 2019 Sep 17;10(1):4223. doi: 10.1038/s41467-019-11982-4. Link to article on publisher's site
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
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This work is licensed under a Creative Commons Attribution 4.0 License.