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Hydrogen Sulfide Stimulates Ischemic Vascular Remodeling Through Nitric Oxide Synthase and Nitrite Reduction Activity Regulating Hypoxia‐Inducible Factor‐1α and Vascular Endothelial Growth Factor–Dependent Angiogenesis
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Abstract
Background Hydrogen sulfide (H[SUB]2[/SUB]S) therapy is recognized as a modulator of vascular function during tissue ischemia with the notion of potential interactions of nitric oxide (NO) metabolism. However, little is known about specific biochemical mechanisms or the importance of H[SUB]2[/SUB]S activation of NO metabolism during ischemic tissue vascular remodeling. The goal of this study was to determine the effect of H[SUB]2[/SUB]S on NO metabolism during chronic tissue ischemia and subsequent effects on ischemic vascular remodeling responses.
Methods and Results The unilateral, permanent femoral artery ligation model of hind‐limb ischemia was performed in C57BL/6J wild‐type and endothelial NO synthase–knockout mice to evaluate exogenous H[SUB]2[/SUB]S effects on NO bioavailability and ischemic revascularization. We found that H[SUB]2[/SUB]S selectively restored chronic ischemic tissue function and viability by enhancing NO production involving both endothelial NO synthase and nitrite reduction mechanisms. Importantly, H[SUB]2[/SUB]S increased ischemic tissue xanthine oxidase activity, hind‐limb blood flow, and angiogenesis, which were blunted by the xanthine oxidase inhibitor febuxostat. H[SUB]2[/SUB]S treatment increased ischemic tissue and endothelial cell hypoxia‐inducible factor‐1α expression and activity and vascular endothelial growth factor protein expression and function in a NO‐dependent manner that was required for ischemic vascular remodeling.
Conclusions These data demonstrate that H[SUB]2[/SUB]S differentially regulates NO metabolism during chronic tissue ischemia, highlighting novel biochemical pathways to increase NO bioavailability for ischemic vascular remodeling.
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http://jaha.ahajournals.org/content/1/5/e004093.full
- Original Research
- Vascular Medicine
- Shyamal C. Bir, MBBS, PhD;
- Gopi K. Kolluru, PhD;
- Paul McCarthy, MD;
- Xinggui Shen, PhD;
- Sibile Pardue, MS;
- Christopher B. Pattillo, PhD;
- Christopher G. Kevil, PhD
- <address>Departments of Pathology and Medicine, LSU Health Sciences Center–Shreveport, Shreveport, LA</address>
- Correspondence to:
Christopher Kevil, PhD, Department of Pathology, LSU Health Sciences Center-Shreveport, 1501 Kings Hwy, Shreveport, LA 71130. E-mail ckevil@lsuhsc.edu
Next Section
Abstract
Background Hydrogen sulfide (H[SUB]2[/SUB]S) therapy is recognized as a modulator of vascular function during tissue ischemia with the notion of potential interactions of nitric oxide (NO) metabolism. However, little is known about specific biochemical mechanisms or the importance of H[SUB]2[/SUB]S activation of NO metabolism during ischemic tissue vascular remodeling. The goal of this study was to determine the effect of H[SUB]2[/SUB]S on NO metabolism during chronic tissue ischemia and subsequent effects on ischemic vascular remodeling responses.
Methods and Results The unilateral, permanent femoral artery ligation model of hind‐limb ischemia was performed in C57BL/6J wild‐type and endothelial NO synthase–knockout mice to evaluate exogenous H[SUB]2[/SUB]S effects on NO bioavailability and ischemic revascularization. We found that H[SUB]2[/SUB]S selectively restored chronic ischemic tissue function and viability by enhancing NO production involving both endothelial NO synthase and nitrite reduction mechanisms. Importantly, H[SUB]2[/SUB]S increased ischemic tissue xanthine oxidase activity, hind‐limb blood flow, and angiogenesis, which were blunted by the xanthine oxidase inhibitor febuxostat. H[SUB]2[/SUB]S treatment increased ischemic tissue and endothelial cell hypoxia‐inducible factor‐1α expression and activity and vascular endothelial growth factor protein expression and function in a NO‐dependent manner that was required for ischemic vascular remodeling.
Conclusions These data demonstrate that H[SUB]2[/SUB]S differentially regulates NO metabolism during chronic tissue ischemia, highlighting novel biochemical pathways to increase NO bioavailability for ischemic vascular remodeling.
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http://jaha.ahajournals.org/content/1/5/e004093.full