Improvement in asymmetric dimethylarginine and oxidative stress in patients with limb salvage after autologous mononuclear stem cell application for critical limb ischemia
Abstract Background Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, acts as an inhibitor of angiogenesis and is associated with an increased risk of cardiovascular mortality. Administration of stem cells may affect endogenous mechanisms that regulate ADMA produc...
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doaj-8f41f8f749b3438aa73cf3bf74517b9b2020-11-24T21:03:47ZengBMCStem Cell Research & Therapy1757-65122017-07-01811710.1186/s13287-017-0622-2Improvement in asymmetric dimethylarginine and oxidative stress in patients with limb salvage after autologous mononuclear stem cell application for critical limb ischemiaJuraj Madaric0Martina Valachovicova1Ludovit Paulis2Jana Pribojova3Renata Mateova4Katarina Sebekova5Luba Postulkova6Terezia Madaricova7Maria Bucova8Martin Mistrik9Ivan Vulev10National Institute of Cardiovascular Diseases, Slovak Medical UniversitySlovak Medical UniversityInstitute of Molecular BioMedicine, Faculty of Medicine Comenius UniversitySlovak Medical UniversitySlovak Medical UniversityInstitute of Molecular BioMedicine, Faculty of Medicine Comenius UniversityNational Institute of Cardiovascular Diseases, Slovak Medical UniversityNational Institute of Cardiovascular Diseases, Slovak Medical UniversityInstitute of Imunology, Faculty of Medicine Comenius UniversityClinic of Haematology and Transfusiology, Faculty HospitalNational Institute of Cardiovascular Diseases, Slovak Medical UniversityAbstract Background Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, acts as an inhibitor of angiogenesis and is associated with an increased risk of cardiovascular mortality. Administration of stem cells may affect endogenous mechanisms that regulate ADMA production and metabolism. The aim of the present study was to analyze ADMA concentration and changes in oxidative stress in patients with advanced critical limb ischemia (CLI) after bone marrow-derived mononuclear cell (BM-MNC) therapy. Methods Fifty patients (age 64 ± 11 years, 44 males, 6 females) with advanced CLI (Rutherford category 5 or 6) not eligible for revascularization were treated by intramuscular (n = 25) or intra-arterial (n = 25) injection of 40 ml BM-MNC concentrate. Patients with limb salvage and improved wound healing after 6 months were considered responders to cell therapy. The concentrations of markers of oxidative stress and angiogenesis were analyzed before, and at 3 and 6 months after BM-MNC delivery. Results At 6-month follow-up, four patients died of reasons unrelated to stem cell therapy. Among the survivors, 80% (37/46) showed limb salvage and improved wound healing. At 6 months follow-up, ADMA concentration significantly decreased in patients with limb salvage (1.74 ± 0.66 to 0.90 ± 0.49 μmol/L, p < 0.001), in parallel with decreased tumor necrosis factor (TNF)-α (2.22 ± 0.16 to 1.94 ± 0.38 pg/ml, p < 0.001), and increased reduced glutathione (6.96 ± 3.1 to 8.67 ± 4.2 μmol/L, p = 0.02), superoxide dismutase activity (168 ± 50 to 218 ± 37 U/L, p = 0.002), and coenzyme Q10 concentration (468 ± 182 to 598 ± 283 μg/L, p = 0.02). The number of delivered BM-MNCs significantly correlated with the decrease in ADMA concentration at 3 months (p = 0.004, r = −0.48) and the decrease in TNF-α concentration at 6 months (p = 0.03, r = −0.44) after cell delivery. ADMA or TNF-α improvement did not correlate with the number of applied CD34+ cells, C-reactive protein concentration, leukocyte count, or the dose of atorvastatin. Conclusions The therapeutic benefit of BM-MNC therapy is associated with reduced ADMA levels and oxidative stress. Regulation of the ADMA-nitric oxide axis and improved antioxidant status may be involved in the beneficial effects of stem cell therapy. Trial registration The study was approved and retrospectively registered by ISRCTN registry, ISRCTN16096154 . Registered on 26 July 2016.http://link.springer.com/article/10.1186/s13287-017-0622-2Cell therapyOxidative stressAsymmetric dimethylarginineAngiogenesisCritical limb ischemia |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Juraj Madaric Martina Valachovicova Ludovit Paulis Jana Pribojova Renata Mateova Katarina Sebekova Luba Postulkova Terezia Madaricova Maria Bucova Martin Mistrik Ivan Vulev |
spellingShingle |
Juraj Madaric Martina Valachovicova Ludovit Paulis Jana Pribojova Renata Mateova Katarina Sebekova Luba Postulkova Terezia Madaricova Maria Bucova Martin Mistrik Ivan Vulev Improvement in asymmetric dimethylarginine and oxidative stress in patients with limb salvage after autologous mononuclear stem cell application for critical limb ischemia Stem Cell Research & Therapy Cell therapy Oxidative stress Asymmetric dimethylarginine Angiogenesis Critical limb ischemia |
author_facet |
Juraj Madaric Martina Valachovicova Ludovit Paulis Jana Pribojova Renata Mateova Katarina Sebekova Luba Postulkova Terezia Madaricova Maria Bucova Martin Mistrik Ivan Vulev |
author_sort |
Juraj Madaric |
title |
Improvement in asymmetric dimethylarginine and oxidative stress in patients with limb salvage after autologous mononuclear stem cell application for critical limb ischemia |
title_short |
Improvement in asymmetric dimethylarginine and oxidative stress in patients with limb salvage after autologous mononuclear stem cell application for critical limb ischemia |
title_full |
Improvement in asymmetric dimethylarginine and oxidative stress in patients with limb salvage after autologous mononuclear stem cell application for critical limb ischemia |
title_fullStr |
Improvement in asymmetric dimethylarginine and oxidative stress in patients with limb salvage after autologous mononuclear stem cell application for critical limb ischemia |
title_full_unstemmed |
Improvement in asymmetric dimethylarginine and oxidative stress in patients with limb salvage after autologous mononuclear stem cell application for critical limb ischemia |
title_sort |
improvement in asymmetric dimethylarginine and oxidative stress in patients with limb salvage after autologous mononuclear stem cell application for critical limb ischemia |
publisher |
BMC |
series |
Stem Cell Research & Therapy |
issn |
1757-6512 |
publishDate |
2017-07-01 |
description |
Abstract Background Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, acts as an inhibitor of angiogenesis and is associated with an increased risk of cardiovascular mortality. Administration of stem cells may affect endogenous mechanisms that regulate ADMA production and metabolism. The aim of the present study was to analyze ADMA concentration and changes in oxidative stress in patients with advanced critical limb ischemia (CLI) after bone marrow-derived mononuclear cell (BM-MNC) therapy. Methods Fifty patients (age 64 ± 11 years, 44 males, 6 females) with advanced CLI (Rutherford category 5 or 6) not eligible for revascularization were treated by intramuscular (n = 25) or intra-arterial (n = 25) injection of 40 ml BM-MNC concentrate. Patients with limb salvage and improved wound healing after 6 months were considered responders to cell therapy. The concentrations of markers of oxidative stress and angiogenesis were analyzed before, and at 3 and 6 months after BM-MNC delivery. Results At 6-month follow-up, four patients died of reasons unrelated to stem cell therapy. Among the survivors, 80% (37/46) showed limb salvage and improved wound healing. At 6 months follow-up, ADMA concentration significantly decreased in patients with limb salvage (1.74 ± 0.66 to 0.90 ± 0.49 μmol/L, p < 0.001), in parallel with decreased tumor necrosis factor (TNF)-α (2.22 ± 0.16 to 1.94 ± 0.38 pg/ml, p < 0.001), and increased reduced glutathione (6.96 ± 3.1 to 8.67 ± 4.2 μmol/L, p = 0.02), superoxide dismutase activity (168 ± 50 to 218 ± 37 U/L, p = 0.002), and coenzyme Q10 concentration (468 ± 182 to 598 ± 283 μg/L, p = 0.02). The number of delivered BM-MNCs significantly correlated with the decrease in ADMA concentration at 3 months (p = 0.004, r = −0.48) and the decrease in TNF-α concentration at 6 months (p = 0.03, r = −0.44) after cell delivery. ADMA or TNF-α improvement did not correlate with the number of applied CD34+ cells, C-reactive protein concentration, leukocyte count, or the dose of atorvastatin. Conclusions The therapeutic benefit of BM-MNC therapy is associated with reduced ADMA levels and oxidative stress. Regulation of the ADMA-nitric oxide axis and improved antioxidant status may be involved in the beneficial effects of stem cell therapy. Trial registration The study was approved and retrospectively registered by ISRCTN registry, ISRCTN16096154 . Registered on 26 July 2016. |
topic |
Cell therapy Oxidative stress Asymmetric dimethylarginine Angiogenesis Critical limb ischemia |
url |
http://link.springer.com/article/10.1186/s13287-017-0622-2 |
work_keys_str_mv |
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