Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis.
Chronic tissue ischemia due to defective vascular perfusion is a hallmark feature of peripheral artery disease for which minimal therapeutic options exist. We have reported that sodium nitrite therapy exerts cytoprotective effects against acute ischemia/reperfusion injury in both heart and liver, consistent with the model of bioactive NO formation from nitrite during ischemic stress. Here, we test the hypothesis that chronic sodium nitrite therapy can selectively augment angiogenic activity and tissue perfusion in the murine hind-limb ischemia model. Various therapeutic doses (8.25-3,300 mug/kg) of sodium nitrite or PBS were administered. Sodium nitrite significantly restored ischemic hind-limb blood flow in a time-dependent manner, with low-dose sodium nitrite being most effective. Nitrite therapy significantly increased ischemic limb vascular density and stimulated endothelial cell proliferation. Remarkably, the effects of sodium nitrite therapy were evident within 3 days of the ischemic insult demonstrating the potency and efficacy of chronic sodium nitrite therapy. Sodium nitrite therapy also increased ischemic tissue nitrite and NO metabolites compared to nonischemic limbs. Use of the NO scavenger carboxy PTIO completely abolished sodium nitrite-dependent ischemic tissue blood flow and angiogenic activity consistent with nitrite reduction to NO being the proangiogenic mechanism. These data demonstrate that chronic sodium nitrite therapy is a recently discovered therapeutic treatment for peripheral artery disease and critical limb ischemia.
Departments of Pathology and Cardiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
Dinesh
D
Kumar
Billy G
BG
Branch
Christopher B
CB
Pattillo
Jay
J
Hood
Stephen
S
Thoma
Stephen
S
Simpson
Sandra
S
Illum
Neeraj
N
Arora
John H
JH
Chidlow
Will
W
Langston
Xinjun
X
Teng
David J
DJ
Lefer
Rakesh P
RP
Patel
Christopher G
CG
Kevil
D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000254:growth & development; D003497:Cyclic N-Oxides / Q000494:pharmacology; D019610:Cytoprotection; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006614:Hindlimb / Q000098:blood supply*; D007093:Imidazoles / Q000494:pharmacology; D007511:Ischemia / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D016491:Peripheral Vascular Diseases / Q000188:drug therapy; D012977:Sodium Nitrite / Q000008:administration & dosage* / Q000627:therapeutic use
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D007093:Imidazoles; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D009569:Nitric Oxide; D012977:Sodium Nitrite