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Anti‐Angiogenic Role of Glutaredoxin‐1 in Hind Limb Ischemia
Author(s) -
Watanabe Yosuke,
Murdoch Colin,
Cohen Richard,
Matsui Reiko
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.889.8
Subject(s) - glutaredoxin , arteriogenesis , glutathione , microbiology and biotechnology , chemistry , ischemia , biochemistry , pathology , medicine , biology , enzyme
Physiological levels of reactive oxygen species (ROS) may alter protein functions by forming S‐glutathione (GSH adducts) on cysteine thiols. Glutaredoxin‐1 (Glrx) regulates protein functions by removing GSH adducts. We previously showed that Glrx overexpression attenuated angiogenic properties in endothelial cells (EC) and impaired in vivo revascularization after hind limb ischemia (HLI). We further generated endothelial specific Glrx overexpressing (EC‐Glrx TG) mice by breeding VECadherin‐tTA and tet‐operated Glrx mice (DOX‐Off ). EC‐Glrx TG mice were treated with doxycycline (DOX) until 8 weeks of age and HLI was performed after 8 weeks of DOX withdrawal. Blood flow recovery was significantly impaired in EC‐Glrx TG mice compared with control mice after HLI surgery (12% vs 39% at 7 days, p<0.01), and 40% of ischemia limbs became necrotic in 2 weeks in EC‐Glrx TG mice, while all limbs survived in control mice. Subcutaneous implants of Matrigel containing VEGF indicated impaired angiogenic potential in EC‐Glrx TG mice. In contrast, blood flow recovery was improved in global Glrx knockout (KO) mice (57% in KO vs 42% in WT at 7 days, p<0.01). Deletion of myeloid Glrx by bone marrow transplantation did not influence blood flow recovery after HLI. In WT mice protein GSH adducts detected by Western blot were increased in ischemic muscle compared to non‐ischemic muscle in association with lower Glrx expression at 3 days after HLI, and the levels of GSH adducts were further increased in the ischemic muscle from Glrx KO mice. These data indicate Glrx in EC, but not in myeloid cells, inhibits angiogenesis and impairs revascularization after HLI, and ROS‐induced GSH adducts on Glrx target protein(s) promote angiogenic signaling after ischemia.