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

Autor: Kant S; Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01655, USA. skant1@bwh.harvard.edu.; Division of Cardiovascular Medicine, Department of Medicine, Brigham Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. skant1@bwh.harvard.edu., Craige SM; Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01655, USA.; Human Nutrition, Foods, and Exercise, Virginia Tech, VA, 24061, USA., Chen K; Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01655, USA.; Department of Medicine, University of Connecticut Health Center, Farmington, CT, 06030, USA., Reif MM; Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01655, USA.; University of Maryland School of Medicine, Baltimore, MD, 21201, USA., Learnard H; Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01655, USA., Kelly M; Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01655, USA., Caliz AD; Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01655, USA.; Division of Cardiovascular Medicine, Department of Medicine, Brigham Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA., Tran KV; Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01655, USA., Ramo K; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01655, USA., Peters OM; Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA, 01655, USA.; Cardiff University, School of Biosciences, Cardiff, CF10 3AX, UK., Freeman M; Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA, 01655, USA.; The Vollum Institute Oregon Health & Science University, Portland, OR, USA., Davis RJ; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01655, USA.; Howard Hughes Medical Institute, Worcester, MA, 01605, USA., Keaney JF Jr; Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01655, USA. jfkeaney@bwh.harvard.edu.; Division of Cardiovascular Medicine, Department of Medicine, Brigham Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. jfkeaney@bwh.harvard.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2019 Sep 17; Vol. 10 (1), pp. 4223. Date of Electronic Publication: 2019 Sep 17.
DOI: 10.1038/s41467-019-11982-4
Abstrakt: 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.
Databáze: MEDLINE