Abstract 318: Jnk3 Regulates Angiogenesis via a Sirtuin1, Creb1 Axis in Peripheral Tissue

Peripheral artery disease (PAD) affects nearly 10 million people in the United States alone, yet patients with clinical manifestations of PAD (e.g. claudication and limb ischemia) have limited and ineffective treatment options. In ischemic tissues, stress kinases, c-Jun N-terminal kinase (JNK), are activated. Here we show that inhibition of the JNK3 isoform, which is most highly expressed in the peripheral nerves, strikingly potentiates angiogenesis and blood flow recovery from mouse hind limb ischemia. JNK3 deficiency leads to increased pro-angiogenetic growth factors such as Vegfa , Pdgfb , Pgf , Hbegf and Tgfb3 in ischemic muscle and cells by repression of the transcription factor Creb1. JNK3 acts through sirtuin 1 (SirT1) to suppress the activity of Creb1. With Sirt1 suppression, as in JNK3 -deficient mice, Creb1 is more active and upregulates pro-angiogenic factors. Together these data suggest that the JNK3/Sirtuin1/Creb1 axis coordinate the vascular remodeling response in peripheral ischemia.