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Gclm Null Mice have Drastically Increased Angiogenic Potential
Author(s) -
Pattillo Christopher B,
Pardue Sibile,
Kavanagh Terrance J,
Kevil Christopher G
Publication year - 2009
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.23.1_supplement.592.12
Subject(s) - gclm , gclc , angiogenesis , glutathione , microbiology and biotechnology , medicine , ligation , biology , endocrinology , chemistry , biochemistry , enzyme
Previous studies have provided evidence that increased levels of glutathione (GSH) attenuate VEGF‐A induced cellular ROS production, thereby decreasing cell motility. The rate limiting step in GSH production is carried out by the holoenzyme glutamate‐cysteine ligase (GCL) which is composed of catalytic (Gclc) and modifier (Gclm) subunits. A mouse Gclm null model has been developed with tissue levels of GSH between 9 and 40% of wild type (WT) mice. This null model was employed to determine the role Gclm plays in redox regulation of angiogenesis following hind limb ischemia. The ischemic leg in the Gclm null mice had blood flows returning to pre‐ligation values by day 7, whereas WT blood flow had not recovered 21 days post‐ligation, indicating an increased cellular proliferation and migration in Gclm null mice. The angiogenic index in Gclm null mice was 2 fold higher in ischemic tissue compared with non‐ischemic tissue. The proliferative index was approximately 1 in ischemic tissue indicating that the proliferating cells were likely endothelial cells. Protein carbonyls were elevated, while GSH levels were depressed in the Gclm null mice. Together, these data provide strong evidence that Gclm null mice have a more intense angiogenic response to ischemia than WT mice. This may be due to increased VEGF‐A/NADPH oxidase signaling in these mice.