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

• Published in: Nature communications Vol. 10; no. 1; pp. 4223 - 14
• Main Authors: Kant, Shashi, Craige, Siobhan M., Chen, Kai, Reif, Michaella M., Learnard, Heather, Kelly, Mark, Caliz, Amada D., Tran, Khanh-Van, Ramo, Kasmir, Peters, Owen M., Freeman, Marc, Davis, Roger J., Keaney, John F.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.09.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 14/1; 14/63; 38/77; 38/90; 631/443/592/75/593/1920; 631/80/304; 82/80; Animals; Blood flow; c-Jun protein; Cardiovascular diseases; Cyclic AMP Response Element-Binding Protein - genetics; Cyclic AMP Response Element-Binding Protein - metabolism; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - metabolism; EGR-1 protein; Forkhead Box Protein O3 - genetics; Forkhead Box Protein O3 - metabolism; Forkhead protein; FOXO3 protein; Growth factors; Hindlimb - blood supply; Hindlimb - innervation; Hindlimb - metabolism; Humanities and Social Sciences; Humans; Ischemia; Ischemia - genetics; Ischemia - metabolism; Ischemia - physiopathology; JNK protein; JNK3 protein; Kinases; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 10 - genetics; Mitogen-Activated Protein Kinase 10 - metabolism; multidisciplinary; Muscle, Skeletal - metabolism; Muscles; Neurons - metabolism; Recovery; Regional Blood Flow; Regulators; Science; Science (multidisciplinary); Signal Transduction; Transcription activation; Transcription factors; Vascular diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11982-4

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. Stress kinases are activated in peripheral ischemic tissues in the presence of vascular diseases. Here the authors show that inhibition of the neural JNK3 kinase improves recovery from hind limb ischemia in animals through activation of the transcription factors Egr1/Creb1 and upregulation of growth factors.