Abstract 15616: Interleukin-21 Receptor Activation: A New Therapeutic Strategy for Peripheral Arterial Disease
Background: Surgical hind-limb ischemia (HLI) in mice has evolved to become an invaluable preclinical model for peripheral arterial disease (PAD). Work from other groups and us, have shown different outcomes across inbred mouse strains, and identified a region on the short arm of mouse chromosome 7 (termed LSq-1) influences the extent of recovery after HLI. The interleukin (IL)-21 receptor (Il21r) lies at the peak of this region.
Methods and Results: The expression level of Il21r is significantly higher following HLI in C57BL/6 mice (~52-fold after 3 days, P=0.01), a strain with good recovery, but not in BALB/c mice, a strain with poor perfusion recovery. Compared to their wide-type (WT) littermates, Il21r-/- in C57BL/6 background have poorer recovery as determined by laser Doppler imaging (perfusion recovery: 74.7±2.1% vs. 58.4±3.7%; n=9~12; P<0.01) and less capillary densities from histological analysis at day 21 post-HLI. In-vivo inactivation of IL21R by treating C57BL/6 mice with IL21R Fc chimera (a fusion protein which blocks IL-21 binding to IL-21 receptor), also results in less perfusion recovery compared with the vehicle treated group 14 days after HLI (perfusion recovery: 85.3±3.6% vs. 69.6±3.31%; n=12; P=0.002). IL21R expression was also detected on endothelia cells by immunofluorescence of ischemic hind-limb tissue from C57BL/6 mice and human PAD patients. Endothelial cells (EC) isolated from ischemic hind-limb tissue shows a higher Il21r expression when compared to EC from non-ischemic limb (8-fold after 7 days, P=0.01). In-vitro, IL21R expression in EC was significantly elevated after hypoxia plus nutrient deprivation (10-fold after 24h, P<0.001). Using conditions with IL-21R up-regulation, treatment of EC with IL-21 increased cell viability and tube formation, decreased cell apoptosis, and increased STAT3 phosphorylation and Bcl-2 expression.
Conclusions: Our data indicate that Il21r up-regulation in response to ischemia is adaptive, and the activation of IL-21 receptor via STAT3 activation may help perfusion recovery by limiting/preventing apoptosis and/or favoring cell survival and angiogenesis, which should be explored as a treatment for PAD.
Author Disclosures: T. Wang: None. A. Cunningham: None. S. Hazarika: None. J.R. Lye: None. W.J. Leonard: None. B.H. Annex: None.
- © 2014 by American Heart Association, Inc.