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

Shashi Kant (), Siobhan M. Craige, Kai Chen, Michaella M. Reif, Heather Learnard, Mark Kelly, Amada D. Caliz, Khanh- Van Tran, Kasmir Ramo, Owen M. Peters, Marc Freeman, Roger J. Davis and John F. Keaney ()
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Shashi Kant: University of Massachusetts Medical School
Siobhan M. Craige: University of Massachusetts Medical School
Kai Chen: University of Massachusetts Medical School
Michaella M. Reif: University of Massachusetts Medical School
Heather Learnard: University of Massachusetts Medical School
Mark Kelly: University of Massachusetts Medical School
Amada D. Caliz: University of Massachusetts Medical School
Khanh- Van Tran: University of Massachusetts Medical School
Kasmir Ramo: University of Massachusetts Medical School
Owen M. Peters: University of Massachusetts Medical School
Marc Freeman: University of Massachusetts Medical School
Roger J. Davis: University of Massachusetts Medical School
John F. Keaney: University of Massachusetts Medical School

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11982-4

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