TY - JOUR
T1 - The nitric oxide system in peripheral artery disease
T2 - Connection with oxidative stress and biopterins
AU - Ismaeel, Ahmed
AU - Papoutsi, Evlampia
AU - Miserlis, Dimitrios
AU - Lavado, Ramon
AU - Haynatzki, Gleb
AU - Casale, George P.
AU - Bohannon, William T.
AU - Smith, Robert S.
AU - Eidson, Jack Leigh
AU - Brumberg, Robert
AU - Hayson, Aaron
AU - Kirk, Jeffrey S.
AU - Castro, Carlos
AU - Sawicki, Ian
AU - Konstantinou, Charalambos
AU - Brewster, Luke P.
AU - Pipinos, Iraklis I.
AU - Koutakis, Panagiotis
N1 - Funding Information:
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.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 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.).
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
KW - Dihydrobiopterin
KW - Endothelial dysfunction
KW - Tetrahydrobiopterin
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U2 - 10.3390/antiox9070590
DO - 10.3390/antiox9070590
M3 - Article
AN - SCOPUS:85087553761
VL - 9
SP - 1
EP - 16
JO - Antioxidants
JF - Antioxidants
SN - 2076-3921
IS - 7
M1 - 590
ER -