title: Endothelial interleukin-21 receptor up-regulation in peripheral artery disease.
abstract: In most patients with symptomatic peripheral artery disease (PAD), severe stenosis in or occlusion of the major blood vessels that supply the legs make the amount of distal blood flow dependent on the capacity to induce angiogenesis and collateral vessel formation. Currently, there are no medications that improve perfusion to the ischemic limb, and thus directly treat the primary problem of PAD. A recent report from our group in a pre-clinical mouse PAD model showed that interleukin-21 receptor (IL-21R) is up-regulated in the endothelial cells from ischemic hindlimb muscle. We further showed that loss of IL-21R resulted in impaired perfusion recovery in this model. In our study, we sought to determine whether IL-21R is present in the endothelium from ischemic muscle of patients with PAD. Using human gastrocnemius muscle biopsies, we found increased levels of IL-21R in the skeletal muscle endothelial cells of patients with PAD compared to control individuals. Interestingly, PAD patients had approximately 1.7-fold higher levels of circulating IL-21. These data provide direct evidence that the IL-21R pathway is indeed up-regulated in patients with PAD. This pathway may serve as a therapeutic target for modulation.
authors.affiliation: Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA.
authors.forename: Alexis
authors.initials: A
authors.lastname: Cunningham
authors.affiliation: Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Houston
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, USA.
authors.forename: Aditya M
authors.initials: AM
authors.lastname: Sharma
authors.affiliation: Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA.
authors.forename: Lingdan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA.
authors.forename: Ayotunde O
authors.initials: AO
authors.lastname: Dokun
authors.affiliation: Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA.
authors.forename: R John
authors.initials: RJ
authors.lastname: Lye
authors.affiliation: Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Rosanne
authors.initials: R
authors.lastname: Spolski
authors.affiliation: Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.affiliation: Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA Division of Cardiovascular Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, USA annex@virginia.edu.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Annex
mesh_terms: D000368:Aged; D001706:Biopsy; D016022:Case-Control Studies; D042783:Endothelial Cells / Q000737:chemistry*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D053738:Interleukin-21 Receptor alpha Subunit / Q000032:analysis*; D007378:Interleukins / Q000097:blood; D007511:Ischemia / Q000175:diagnosis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply*; D058729:Peripheral Arterial Disease / Q000175:diagnosis / Q000378:metabolism*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation; D000098546:Interleukin-21
chemical_list: C508117:IL21R protein, human; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000098546:Interleukin-21
keywords: IL-2R; PAD; endothelial cells; interleukin-21 receptor; ischemia; peripheral artery disease