Short Communication: Asymmetric Dimethylarginine Impairs Angiogenic Progenitor Cell Function in Patients With Coronary Artery Disease Through a MicroRNA-21–Dependent Mechanism
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- Felix Fleissner
- From the Institute of Molecular and Translational Therapeutic Strategies (F.F., V.J., J.F., S.K.G., T.T.) and the Department of Cardiology and Angiology (F.F., T.T.), Hannover Medical School, Hannover, Germany; King’s College London School of Medicine (X.Y., Q.X., M.M.), Cardiovascular Division, London, United Kingdom; the Department of Medicine I/Cardiology (P.G., G.E., J.B.), Julius-Maximilians-University, Würzburg, Germany; and Microarray Core Facility (S.K.), Interdisciplinary Collaborative...
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- Virginija Jazbutyte
- From the Institute of Molecular and Translational Therapeutic Strategies (F.F., V.J., J.F., S.K.G., T.T.) and the Department of Cardiology and Angiology (F.F., T.T.), Hannover Medical School, Hannover, Germany; King’s College London School of Medicine (X.Y., Q.X., M.M.), Cardiovascular Division, London, United Kingdom; the Department of Medicine I/Cardiology (P.G., G.E., J.B.), Julius-Maximilians-University, Würzburg, Germany; and Microarray Core Facility (S.K.), Interdisciplinary Collaborative...
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- Jan Fiedler
- From the Institute of Molecular and Translational Therapeutic Strategies (F.F., V.J., J.F., S.K.G., T.T.) and the Department of Cardiology and Angiology (F.F., T.T.), Hannover Medical School, Hannover, Germany; King’s College London School of Medicine (X.Y., Q.X., M.M.), Cardiovascular Division, London, United Kingdom; the Department of Medicine I/Cardiology (P.G., G.E., J.B.), Julius-Maximilians-University, Würzburg, Germany; and Microarray Core Facility (S.K.), Interdisciplinary Collaborative...
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- Shashi K. Gupta
- From the Institute of Molecular and Translational Therapeutic Strategies (F.F., V.J., J.F., S.K.G., T.T.) and the Department of Cardiology and Angiology (F.F., T.T.), Hannover Medical School, Hannover, Germany; King’s College London School of Medicine (X.Y., Q.X., M.M.), Cardiovascular Division, London, United Kingdom; the Department of Medicine I/Cardiology (P.G., G.E., J.B.), Julius-Maximilians-University, Würzburg, Germany; and Microarray Core Facility (S.K.), Interdisciplinary Collaborative...
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- Xiaoke Yin
- From the Institute of Molecular and Translational Therapeutic Strategies (F.F., V.J., J.F., S.K.G., T.T.) and the Department of Cardiology and Angiology (F.F., T.T.), Hannover Medical School, Hannover, Germany; King’s College London School of Medicine (X.Y., Q.X., M.M.), Cardiovascular Division, London, United Kingdom; the Department of Medicine I/Cardiology (P.G., G.E., J.B.), Julius-Maximilians-University, Würzburg, Germany; and Microarray Core Facility (S.K.), Interdisciplinary Collaborative...
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- Qingbo Xu
- From the Institute of Molecular and Translational Therapeutic Strategies (F.F., V.J., J.F., S.K.G., T.T.) and the Department of Cardiology and Angiology (F.F., T.T.), Hannover Medical School, Hannover, Germany; King’s College London School of Medicine (X.Y., Q.X., M.M.), Cardiovascular Division, London, United Kingdom; the Department of Medicine I/Cardiology (P.G., G.E., J.B.), Julius-Maximilians-University, Würzburg, Germany; and Microarray Core Facility (S.K.), Interdisciplinary Collaborative...
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- Paolo Galuppo
- From the Institute of Molecular and Translational Therapeutic Strategies (F.F., V.J., J.F., S.K.G., T.T.) and the Department of Cardiology and Angiology (F.F., T.T.), Hannover Medical School, Hannover, Germany; King’s College London School of Medicine (X.Y., Q.X., M.M.), Cardiovascular Division, London, United Kingdom; the Department of Medicine I/Cardiology (P.G., G.E., J.B.), Julius-Maximilians-University, Würzburg, Germany; and Microarray Core Facility (S.K.), Interdisciplinary Collaborative...
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- Susanne Kneitz
- From the Institute of Molecular and Translational Therapeutic Strategies (F.F., V.J., J.F., S.K.G., T.T.) and the Department of Cardiology and Angiology (F.F., T.T.), Hannover Medical School, Hannover, Germany; King’s College London School of Medicine (X.Y., Q.X., M.M.), Cardiovascular Division, London, United Kingdom; the Department of Medicine I/Cardiology (P.G., G.E., J.B.), Julius-Maximilians-University, Würzburg, Germany; and Microarray Core Facility (S.K.), Interdisciplinary Collaborative...
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- Manuel Mayr
- From the Institute of Molecular and Translational Therapeutic Strategies (F.F., V.J., J.F., S.K.G., T.T.) and the Department of Cardiology and Angiology (F.F., T.T.), Hannover Medical School, Hannover, Germany; King’s College London School of Medicine (X.Y., Q.X., M.M.), Cardiovascular Division, London, United Kingdom; the Department of Medicine I/Cardiology (P.G., G.E., J.B.), Julius-Maximilians-University, Würzburg, Germany; and Microarray Core Facility (S.K.), Interdisciplinary Collaborative...
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- Georg Ertl
- From the Institute of Molecular and Translational Therapeutic Strategies (F.F., V.J., J.F., S.K.G., T.T.) and the Department of Cardiology and Angiology (F.F., T.T.), Hannover Medical School, Hannover, Germany; King’s College London School of Medicine (X.Y., Q.X., M.M.), Cardiovascular Division, London, United Kingdom; the Department of Medicine I/Cardiology (P.G., G.E., J.B.), Julius-Maximilians-University, Würzburg, Germany; and Microarray Core Facility (S.K.), Interdisciplinary Collaborative...
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- Johann Bauersachs
- From the Institute of Molecular and Translational Therapeutic Strategies (F.F., V.J., J.F., S.K.G., T.T.) and the Department of Cardiology and Angiology (F.F., T.T.), Hannover Medical School, Hannover, Germany; King’s College London School of Medicine (X.Y., Q.X., M.M.), Cardiovascular Division, London, United Kingdom; the Department of Medicine I/Cardiology (P.G., G.E., J.B.), Julius-Maximilians-University, Würzburg, Germany; and Microarray Core Facility (S.K.), Interdisciplinary Collaborative...
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- Thomas Thum
- From the Institute of Molecular and Translational Therapeutic Strategies (F.F., V.J., J.F., S.K.G., T.T.) and the Department of Cardiology and Angiology (F.F., T.T.), Hannover Medical School, Hannover, Germany; King’s College London School of Medicine (X.Y., Q.X., M.M.), Cardiovascular Division, London, United Kingdom; the Department of Medicine I/Cardiology (P.G., G.E., J.B.), Julius-Maximilians-University, Würzburg, Germany; and Microarray Core Facility (S.K.), Interdisciplinary Collaborative...
説明
<jats:p> <jats:bold> <jats:italic> <jats:underline>Rationale</jats:underline> : </jats:italic> </jats:bold> The endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) is increased in patients with coronary artery disease and may regulate function of circulating angiogenic progenitor cells (APCs) by small regulatory RNAs. </jats:p> <jats:p> <jats:bold> <jats:italic> <jats:underline>Objectives</jats:underline> : </jats:italic> </jats:bold> To study the role of microRNAs in ADMA-mediated impairment of APCs. </jats:p> <jats:p> <jats:bold> <jats:italic> <jats:underline>Methods and Results</jats:underline> : </jats:italic> </jats:bold> By using microarray analyses, we established microRNA expression profiles of human APCs. We used ADMA to induce APC dysfunction and found 16 deregulated microRNAs. We focused on <jats:italic>miR-21</jats:italic> , which was 3-fold upregulated by ADMA treatment. Overexpression of <jats:italic>miR-21</jats:italic> in human APCs impaired migratory capacity. To identify regulated <jats:italic>miR-21</jats:italic> targets, we used proteome analysis, using difference in-gel electrophoresis followed by mass spectrometric analysis of regulated proteins. We found that transfection of <jats:italic>miR-21</jats:italic> precursors significantly repressed superoxide dismutase 2 in APCs, which resulted in increased intracellular reactive oxygen species concentration and impaired nitric oxide bioavailability. <jats:italic>MiR-21</jats:italic> further repressed sprouty-2, leading to Erk Map kinase–dependent reactive oxygen species formation and APC migratory defects. Small interference RNA–mediated superoxide dismutase 2 or sprouty-2 reduction also increased reactive oxygen species formation and impaired APC migratory capacity. ADMA-mediated reactive oxygen species formation and APC dysfunction was rescued by <jats:italic>miR-21</jats:italic> blockade. APCs from patients with coronary artery disease and high ADMA plasma levels displayed >4-fold elevated <jats:italic>miR-21</jats:italic> levels, low superoxide dismutase 2 expression, and impaired migratory capacity, which could be normalized by <jats:italic>miR-21</jats:italic> antagonism. </jats:p> <jats:p> <jats:bold> <jats:italic> <jats:underline>Conclusions</jats:underline> : </jats:italic> </jats:bold> We identified a novel <jats:italic>miR-21</jats:italic> –dependent mechanism of ADMA-mediated APC dysfunction. <jats:italic>MiR-21</jats:italic> antagonism therefore emerges as an interesting strategy to improve dysfunctional APCs in patients with coronary artery disease. </jats:p>
収録刊行物
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- Circulation Research
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Circulation Research 107 (1), 138-143, 2010-07-09
Ovid Technologies (Wolters Kluwer Health)