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

Department of Nutrition, Food and Exercise Sciences, Florida State University, Tallahassee, FL 32304, USA
Department of Surgery, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA
Department of Environmental Science, Baylor University, Waco, TX 76798, USA
Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE 68198, USA
Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA
Department of Surgery, Baylor Scott & White Medical Center, Temple, TX 76508, USA
Vascular Surgery Associates, Tallahassee, FL 32308, USA
Department of Vascular Surgery, Capital Regional Medical Center, Tallahassee, FL 32308, USA
Department of Electrical & Computer Engineering, Florida State University, Tallahassee, FL 32310, USA
Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA
Department of Surgery and Research Service, Veterans Affairs-Western Iowa Medical Center, Omaha, NE 68105, USA
Author to whom correspondence should be addressed.
Antioxidants 2020, 9(7), 590;
Received: 27 May 2020 / Revised: 15 June 2020 / Accepted: 1 July 2020 / Published: 6 July 2020
(This article belongs to the Special Issue Oxidative Stress and Inflammation in Cardiovascular Diseases)
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. View Full-Text
Keywords: tetrahydrobiopterin; dihydrobiopterin; endothelial dysfunction tetrahydrobiopterin; dihydrobiopterin; endothelial dysfunction
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MDPI and ACS Style

Ismaeel, A.; Papoutsi, E.; Miserlis, D.; Lavado, R.; Haynatzki, G.; Casale, G.P.; Bohannon, W.T.; Smith, R.S.; Eidson, J.L.; Brumberg, R.; Hayson, A.; Kirk, J.S.; Castro, C.; Sawicki, I.; Konstantinou, C.; Brewster, L.P.; Pipinos, I.I.; Koutakis, P. The Nitric Oxide System in Peripheral Artery Disease: Connection with Oxidative Stress and Biopterins. Antioxidants 2020, 9, 590.

AMA Style

Ismaeel A, Papoutsi E, Miserlis D, Lavado R, Haynatzki G, Casale GP, Bohannon WT, Smith RS, Eidson JL, Brumberg R, Hayson A, Kirk JS, Castro C, Sawicki I, Konstantinou C, Brewster LP, Pipinos II, Koutakis P. The Nitric Oxide System in Peripheral Artery Disease: Connection with Oxidative Stress and Biopterins. Antioxidants. 2020; 9(7):590.

Chicago/Turabian Style

Ismaeel, Ahmed, Evlampia Papoutsi, Dimitrios Miserlis, Ramon Lavado, Gleb Haynatzki, George P. Casale, William T. Bohannon, Robert S. Smith, Jack L. Eidson, Robert Brumberg, Aaron Hayson, Jeffrey S. Kirk, Carlos Castro, Ian Sawicki, Charalambos Konstantinou, Luke P. Brewster, Iraklis I. Pipinos, and Panagiotis Koutakis. 2020. "The Nitric Oxide System in Peripheral Artery Disease: Connection with Oxidative Stress and Biopterins" Antioxidants 9, no. 7: 590.

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