Neural JNK3 regulates blood flow recovery after hindlimb ischemia in mice via an Egr1/Creb1 axis

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dc.contributor.authorKant, Shashien
dc.contributor.authorCraige, Siobhan M.en
dc.contributor.authorChen, Kaien
dc.contributor.authorReif, Michaella M.en
dc.contributor.authorLearnard, Heatheren
dc.contributor.authorKelly, Marken
dc.contributor.authorCaliz, Amada D.en
dc.contributor.authorTran, Khanh-Vanen
dc.contributor.authorRamo, Kasmiren
dc.contributor.authorPeters, Owen M.en
dc.contributor.authorFreeman, Marcen
dc.contributor.authorDavis, Roger J.en
dc.contributor.authorKeaney, John F. Jr.en
dc.contributor.departmentHuman Nutrition, Foods, and Exerciseen
dc.date.accessioned2019-11-20T15:32:36Zen
dc.date.available2019-11-20T15:32:36Zen
dc.date.issued2019-09-17en
dc.description.abstractDiseases 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.en
dc.description.notesWe thank Marta DeSourdis, Carol Marble and Donna Cobb for academic assistance and Xiaoyun Huang and Yongmei Pei for technical assistance and Anastassiia Vertii for critical reading. This work was supported by grants 16SDG29660007 from AHA (to S.K.), 5T32HL120823-03 (to K.V.T.), DK107220 (to R.J.D.), and HL092122, HL098407 (to J.F.K.) from NIH.en
dc.description.sponsorshipAHA American Heart Association [16SDG29660007]; NIH United States Department of Health & Human Services National Institutes of Health (NIH) - USA [5T32HL120823-03, DK107220, HL092122, HL098407]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41467-019-11982-4en
dc.identifier.eissn2041-1723en
dc.identifier.other4223en
dc.identifier.pmid31530804en
dc.identifier.urihttp://hdl.handle.net/10919/95818en
dc.identifier.volume10en
dc.language.isoenen
dc.publisherSpringer Natureen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleNeural JNK3 regulates blood flow recovery after hindlimb ischemia in mice via an Egr1/Creb1 axisen
dc.title.serialNature Communicationsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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