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Hydrogen sulfide therapy rescues critical limb ischemia in aged diabetic animals through an eNOS/HIF‐1/VEGF dependent pathway
Author(s) -
Bir Shyamal C,
Pattillo Christopher B,
Shen Xinggui,
Kolluru Gopi krishna,
Lefer David J,
Kevil Christopher G
Publication year - 2011
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.25.1_supplement.1092.6
Subject(s) - tunel assay , ischemia , enos , perfusion , hindlimb , endocrinology , vascular endothelial growth factor , medicine , neovascularization , angiogenesis , arteriogenesis , chemistry , andrology , nitric oxide , vegf receptors , immunohistochemistry , nitric oxide synthase
Objective To determine the effect and molecular mechanism of Na 2 S induced neovascularization in critical limb ischemia (CLI) during diabetes. Methods Permanent unilateral hind limb ischemia was induced in 42 wk old Db/Db diabetic or eNOSKO mice (n=8, each group). PBS or 0.5 mg/kg Na 2 S was administered twice daily by retro‐orbital injection. Body weight, blood glucose, lipid panels, hind limb perfusion, angiogenic index, capillary to myofiber ratio, proliferation index and TUNEL assay were measured. Endothelial cell proliferation was also performed under hypoxic condition. Lastly, HIF ‐1 activity was measured using a HIF ‐1 reporter assay and VEGF expression was determined by ELISA. Result Blood tissue perfusion, angiogenic index, proliferation index, capillary to myofiber ratio, HIF‐1 activity and VEGF expression were all significantly increased and conversely, apoptosis was prevented in ischemic hind limb of aged diabetic mice treated with Na 2 S compared to PBS control. Na 2 S therapy did not completely restore eNOS KO ischemic hind limb blood flow to pre‐ligation levels and cPTIO treatment significantly prevented Na 2 S mediated hypoxic endothelial cell proliferation activity. Conclusion Sodium sulfide therapy restores tissue perfusion of critical limb ischemia in aged diabetic mice by increasing HIF‐1 activation and expression of VEGF that involves NO synthesis and bioavailability.