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Author Notes:

Panagiotis Koutakis Department of Nutrition, Food and Exercise Sciences, Florida State University, Tallahassee, FL 32304, USA; pkoutakis@fsu.edu

Conceptualization, A.I., G.P.C., W.T.B., I.I.P. and P.K.; methodology, A.I., E.P., R.L., D.M., G.P.C., W.T.B., R.S.S., J.L.E., R.B., A.H., J.S.K., C.C., I.S. and L.P.B.; formal analysis, C.K., G.H., A.I., and P.K.; investigation, A.I., E.P., R.L., D.M., W.T.B., R.S.S., J.L.E., R.B., A.H., J.S.K., C.C., I.S. and L.B.; resources, D.M., W.T.B., R.S.S., J.L.E., R.B., A.H., J.S.K., C.C., I.S. and L.P.B.; writing—original draft preparation, A.I., I.I.P. and P.K.; writing—review and editing, A.I., I.I.P., P.K., D.M., G.H. and L.P.B.; visualization, C.K.; supervision, P.K. and I.I.P.; project administration, P.K. and I.I.P.; funding acquisition, P.K., G.P.C. and I.I.P. All authors have read and agreed to the published version of the manuscript.

We would like to thank Leandro Leberon for preparation of the central illustration.

The authors declare no conflict of interest.

Subjects:

Research Funding:

This work was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers R01AG034995 (I.I.P.), R01AG049868 (I.I.P. and G.P.C.) and R01AG064420 (P.K.).

Additionally, the study was supported by the American Heart Association grant #17SDG33630088 (P.K.) and by the Charles and Mary Heider Fund for Excellence in Vascular Surgery (Omaha, NE. USA) (I.I.P.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Chemistry, Medicinal
  • Food Science & Technology
  • Pharmacology & Pharmacy
  • tetrahydrobiopterin
  • dihydrobiopterin
  • endothelial dysfunction
  • GLYCATION END-PRODUCTS
  • FLOW-MEDIATED DILATION
  • ENDOTHELIAL DYSFUNCTION
  • REVASCULARIZATION PROCEDURES
  • INTERMITTENT CLAUDICATION
  • SKIN AUTOFLUORESCENCE
  • CARDIOVASCULAR EVENTS
  • TETRAHYDROBIOPTERIN
  • SYNTHASE
  • DIMETHYLARGININE

The Nitric Oxide System in Peripheral Artery Disease: Connection with Oxidative Stress and Biopterins

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Journal Title:

Antioxidants

Volume:

Volume 9, Number 7

Publisher:

, Pages 1-16

Type of Work:

Article | Final Publisher PDF

Abstract:

Peripheral artery disease (PAD) pathophysiology extends beyond hemodynamics to include other operating mechanisms, including endothelial dysfunction. Oxidative stress may be linked to endothelial dysfunction by reducing nitric oxide (NO) bioavailability. We aimed to investigate whether the NO system and its regulators are altered in the setting of PAD and to assess the relationship between NO bioavailability and oxidative stress. Sera from 35 patients with intermittent claudication (IC), 26 patients with critical limb ischemia (CLI), and 35 non-PAD controls were analyzed to determine levels of tetrahydrobiopterin (BH4), dihydrobiopterin (BH2), nitrate/nitrite (nitric oxides, or NOx), arginine, citrulline, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and the oxidative stress markers 8-Oxo-2′-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE), advanced glycation end products (AGEs), and protein carbonyls. NOx was significantly lower in IC and CLI patients compared to controls in association with elevated oxidative stress, with the greatest NOx reductions observed in CLI. Compared with controls, IC and CLI patients had reduced BH4, elevated BH2, and a reduced BH4/BH2 ratio. SDMA, the arginine/SDMA ratio, and the arginine/ADMA ratio were significantly higher in CLI patients. The NO system and its regulators are significantly compromised in PAD. This dysregulation appears to be driven by increased oxidative stress and worsens as the disease progresses from claudication to CLI.

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© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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