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Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation: Rescue...
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| Zeitschriftentitel: | Circulation Research |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| In: | Circulation Research, 122, 2018, 1, S. 31-46 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Ovid Technologies (Wolters Kluwer Health)
|
| Schlagwörter: |
| author_facet |
Spallotta, Francesco Cencioni, Chiara Atlante, Sandra Garella, Davide Cocco, Mattia Mori, Mattia Mastrocola, Raffaella Kuenne, Carsten Guenther, Stefan Nanni, Simona Azzimato, Valerio Zukunft, Sven Kornberger, Angela Sürün, Duran Schnütgen, Frank von Melchner, Harald Di Stilo, Antonella Aragno, Manuela Braspenning, Maarten van Criekinge, Wim De Blasio, Miles J. Ritchie, Rebecca H. Zaccagnini, Germana Martelli, Fabio Farsetti, Antonella Fleming, Ingrid Braun, Thomas Beiras-Fernandez, Andres Botta, Bruno Collino, Massimo Bertinaria, Massimo Zeiher, Andreas M. Gaetano, Carlo Spallotta, Francesco Cencioni, Chiara Atlante, Sandra Garella, Davide Cocco, Mattia Mori, Mattia Mastrocola, Raffaella Kuenne, Carsten Guenther, Stefan Nanni, Simona Azzimato, Valerio Zukunft, Sven Kornberger, Angela Sürün, Duran Schnütgen, Frank von Melchner, Harald Di Stilo, Antonella Aragno, Manuela Braspenning, Maarten van Criekinge, Wim De Blasio, Miles J. Ritchie, Rebecca H. Zaccagnini, Germana Martelli, Fabio Farsetti, Antonella Fleming, Ingrid Braun, Thomas Beiras-Fernandez, Andres Botta, Bruno Collino, Massimo Bertinaria, Massimo Zeiher, Andreas M. Gaetano, Carlo |
|---|---|
| author |
Spallotta, Francesco Cencioni, Chiara Atlante, Sandra Garella, Davide Cocco, Mattia Mori, Mattia Mastrocola, Raffaella Kuenne, Carsten Guenther, Stefan Nanni, Simona Azzimato, Valerio Zukunft, Sven Kornberger, Angela Sürün, Duran Schnütgen, Frank von Melchner, Harald Di Stilo, Antonella Aragno, Manuela Braspenning, Maarten van Criekinge, Wim De Blasio, Miles J. Ritchie, Rebecca H. Zaccagnini, Germana Martelli, Fabio Farsetti, Antonella Fleming, Ingrid Braun, Thomas Beiras-Fernandez, Andres Botta, Bruno Collino, Massimo Bertinaria, Massimo Zeiher, Andreas M. Gaetano, Carlo |
| spellingShingle |
Spallotta, Francesco Cencioni, Chiara Atlante, Sandra Garella, Davide Cocco, Mattia Mori, Mattia Mastrocola, Raffaella Kuenne, Carsten Guenther, Stefan Nanni, Simona Azzimato, Valerio Zukunft, Sven Kornberger, Angela Sürün, Duran Schnütgen, Frank von Melchner, Harald Di Stilo, Antonella Aragno, Manuela Braspenning, Maarten van Criekinge, Wim De Blasio, Miles J. Ritchie, Rebecca H. Zaccagnini, Germana Martelli, Fabio Farsetti, Antonella Fleming, Ingrid Braun, Thomas Beiras-Fernandez, Andres Botta, Bruno Collino, Massimo Bertinaria, Massimo Zeiher, Andreas M. Gaetano, Carlo Circulation Research Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation Cardiology and Cardiovascular Medicine Physiology |
| author_sort |
spallotta, francesco |
| spelling |
Spallotta, Francesco Cencioni, Chiara Atlante, Sandra Garella, Davide Cocco, Mattia Mori, Mattia Mastrocola, Raffaella Kuenne, Carsten Guenther, Stefan Nanni, Simona Azzimato, Valerio Zukunft, Sven Kornberger, Angela Sürün, Duran Schnütgen, Frank von Melchner, Harald Di Stilo, Antonella Aragno, Manuela Braspenning, Maarten van Criekinge, Wim De Blasio, Miles J. Ritchie, Rebecca H. Zaccagnini, Germana Martelli, Fabio Farsetti, Antonella Fleming, Ingrid Braun, Thomas Beiras-Fernandez, Andres Botta, Bruno Collino, Massimo Bertinaria, Massimo Zeiher, Andreas M. Gaetano, Carlo 0009-7330 1524-4571 Ovid Technologies (Wolters Kluwer Health) Cardiology and Cardiovascular Medicine Physiology http://dx.doi.org/10.1161/circresaha.117.311300 <jats:sec> <jats:title> <jats:underline>Rationale:</jats:underline> </jats:title> <jats:p>Human cardiac mesenchymal cells (CMSCs) are a therapeutically relevant primary cell population. Diabetes mellitus compromises CMSC function as consequence of metabolic alterations and incorporation of stable epigenetic changes.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Objective:</jats:underline> </jats:title> <jats:p>To investigate the role of α-ketoglutarate (αKG) in the epimetabolic control of DNA demethylation in CMSCs.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Methods and Results:</jats:underline> </jats:title> <jats:p>Quantitative global analysis, methylated and hydroxymethylated DNA sequencing, and gene-specific GC methylation detection revealed an accumulation of 5-methylcytosine, 5-hydroxymethylcytosine, and 5-formylcytosine in the genomic DNA of human CMSCs isolated from diabetic donors. Whole heart genomic DNA analysis revealed iterative oxidative cytosine modification accumulation in mice exposed to high-fat diet (HFD), injected with streptozotocin, or both in combination (streptozotocin/HFD). In this context, untargeted and targeted metabolomics indicated an intracellular reduction of αKG synthesis in diabetic CMSCs and in the whole heart of HFD mice. This observation was paralleled by a compromised TDG (thymine DNA glycosylase) and TET1 (ten–eleven translocation protein 1) association and function with TET1 relocating out of the nucleus. Molecular dynamics and mutational analyses showed that αKG binds TDG on Arg275 providing an enzymatic allosteric activation. As a consequence, the enzyme significantly increased its capacity to remove G/T nucleotide mismatches or 5-formylcytosine. Accordingly, an exogenous source of αKG restored the DNA demethylation cycle by promoting TDG function, TET1 nuclear localization, and TET/TDG association. TDG inactivation by CRISPR/Cas9 knockout or TET/TDG siRNA knockdown induced 5-formylcytosine accumulation, thus partially mimicking the diabetic epigenetic landscape in cells of nondiabetic origin. The novel compound (S)-2-[(2,6-dichlorobenzoyl)amino]succinic acid (AA6), identified as an inhibitor of αKG dehydrogenase, increased the αKG level in diabetic CMSCs and in the heart of HFD and streptozotocin mice eliciting, in HFD, DNA demethylation, glucose uptake, and insulin response.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Conclusions:</jats:underline> </jats:title> <jats:p>Restoring the epimetabolic control of DNA demethylation cycle promises beneficial effects on cells compromised by environmental metabolic changes.</jats:p> </jats:sec> Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation Circulation Research |
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10.1161/circresaha.117.311300 |
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Ovid Technologies (Wolters Kluwer Health), 2018 |
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Ovid Technologies (Wolters Kluwer Health), 2018 |
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0009-7330 1524-4571 |
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2018 |
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Ovid Technologies (Wolters Kluwer Health) |
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ai |
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Circulation Research |
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49 |
| title_sub |
Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation |
| title |
Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation |
| title_unstemmed |
Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation |
| title_full |
Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation |
| title_fullStr |
Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation |
| title_full_unstemmed |
Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation |
| title_short |
Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation |
| title_sort |
stable oxidative cytosine modifications accumulate in cardiac mesenchymal cells from type2 diabetes patients : rescue by α-ketoglutarate and tet-tdg functional reactivation |
| topic |
Cardiology and Cardiovascular Medicine Physiology |
| url |
http://dx.doi.org/10.1161/circresaha.117.311300 |
| publishDate |
2018 |
| physical |
31-46 |
| description |
<jats:sec>
<jats:title>
<jats:underline>Rationale:</jats:underline>
</jats:title>
<jats:p>Human cardiac mesenchymal cells (CMSCs) are a therapeutically relevant primary cell population. Diabetes mellitus compromises CMSC function as consequence of metabolic alterations and incorporation of stable epigenetic changes.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>
<jats:underline>Objective:</jats:underline>
</jats:title>
<jats:p>To investigate the role of α-ketoglutarate (αKG) in the epimetabolic control of DNA demethylation in CMSCs.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>
<jats:underline>Methods and Results:</jats:underline>
</jats:title>
<jats:p>Quantitative global analysis, methylated and hydroxymethylated DNA sequencing, and gene-specific GC methylation detection revealed an accumulation of 5-methylcytosine, 5-hydroxymethylcytosine, and 5-formylcytosine in the genomic DNA of human CMSCs isolated from diabetic donors. Whole heart genomic DNA analysis revealed iterative oxidative cytosine modification accumulation in mice exposed to high-fat diet (HFD), injected with streptozotocin, or both in combination (streptozotocin/HFD). In this context, untargeted and targeted metabolomics indicated an intracellular reduction of αKG synthesis in diabetic CMSCs and in the whole heart of HFD mice. This observation was paralleled by a compromised TDG (thymine DNA glycosylase) and TET1 (ten–eleven translocation protein 1) association and function with TET1 relocating out of the nucleus. Molecular dynamics and mutational analyses showed that αKG binds TDG on Arg275 providing an enzymatic allosteric activation. As a consequence, the enzyme significantly increased its capacity to remove G/T nucleotide mismatches or 5-formylcytosine. Accordingly, an exogenous source of αKG restored the DNA demethylation cycle by promoting TDG function, TET1 nuclear localization, and TET/TDG association. TDG inactivation by CRISPR/Cas9 knockout or TET/TDG siRNA knockdown induced 5-formylcytosine accumulation, thus partially mimicking the diabetic epigenetic landscape in cells of nondiabetic origin. The novel compound (S)-2-[(2,6-dichlorobenzoyl)amino]succinic acid (AA6), identified as an inhibitor of αKG dehydrogenase, increased the αKG level in diabetic CMSCs and in the heart of HFD and streptozotocin mice eliciting, in HFD, DNA demethylation, glucose uptake, and insulin response.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>
<jats:underline>Conclusions:</jats:underline>
</jats:title>
<jats:p>Restoring the epimetabolic control of DNA demethylation cycle promises beneficial effects on cells compromised by environmental metabolic changes.</jats:p>
</jats:sec> |
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| author | Spallotta, Francesco, Cencioni, Chiara, Atlante, Sandra, Garella, Davide, Cocco, Mattia, Mori, Mattia, Mastrocola, Raffaella, Kuenne, Carsten, Guenther, Stefan, Nanni, Simona, Azzimato, Valerio, Zukunft, Sven, Kornberger, Angela, Sürün, Duran, Schnütgen, Frank, von Melchner, Harald, Di Stilo, Antonella, Aragno, Manuela, Braspenning, Maarten, van Criekinge, Wim, De Blasio, Miles J., Ritchie, Rebecca H., Zaccagnini, Germana, Martelli, Fabio, Farsetti, Antonella, Fleming, Ingrid, Braun, Thomas, Beiras-Fernandez, Andres, Botta, Bruno, Collino, Massimo, Bertinaria, Massimo, Zeiher, Andreas M., Gaetano, Carlo |
| author_facet | Spallotta, Francesco, Cencioni, Chiara, Atlante, Sandra, Garella, Davide, Cocco, Mattia, Mori, Mattia, Mastrocola, Raffaella, Kuenne, Carsten, Guenther, Stefan, Nanni, Simona, Azzimato, Valerio, Zukunft, Sven, Kornberger, Angela, Sürün, Duran, Schnütgen, Frank, von Melchner, Harald, Di Stilo, Antonella, Aragno, Manuela, Braspenning, Maarten, van Criekinge, Wim, De Blasio, Miles J., Ritchie, Rebecca H., Zaccagnini, Germana, Martelli, Fabio, Farsetti, Antonella, Fleming, Ingrid, Braun, Thomas, Beiras-Fernandez, Andres, Botta, Bruno, Collino, Massimo, Bertinaria, Massimo, Zeiher, Andreas M., Gaetano, Carlo, Spallotta, Francesco, Cencioni, Chiara, Atlante, Sandra, Garella, Davide, Cocco, Mattia, Mori, Mattia, Mastrocola, Raffaella, Kuenne, Carsten, Guenther, Stefan, Nanni, Simona, Azzimato, Valerio, Zukunft, Sven, Kornberger, Angela, Sürün, Duran, Schnütgen, Frank, von Melchner, Harald, Di Stilo, Antonella, Aragno, Manuela, Braspenning, Maarten, van Criekinge, Wim, De Blasio, Miles J., Ritchie, Rebecca H., Zaccagnini, Germana, Martelli, Fabio, Farsetti, Antonella, Fleming, Ingrid, Braun, Thomas, Beiras-Fernandez, Andres, Botta, Bruno, Collino, Massimo, Bertinaria, Massimo, Zeiher, Andreas M., Gaetano, Carlo |
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| description | <jats:sec> <jats:title> <jats:underline>Rationale:</jats:underline> </jats:title> <jats:p>Human cardiac mesenchymal cells (CMSCs) are a therapeutically relevant primary cell population. Diabetes mellitus compromises CMSC function as consequence of metabolic alterations and incorporation of stable epigenetic changes.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Objective:</jats:underline> </jats:title> <jats:p>To investigate the role of α-ketoglutarate (αKG) in the epimetabolic control of DNA demethylation in CMSCs.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Methods and Results:</jats:underline> </jats:title> <jats:p>Quantitative global analysis, methylated and hydroxymethylated DNA sequencing, and gene-specific GC methylation detection revealed an accumulation of 5-methylcytosine, 5-hydroxymethylcytosine, and 5-formylcytosine in the genomic DNA of human CMSCs isolated from diabetic donors. Whole heart genomic DNA analysis revealed iterative oxidative cytosine modification accumulation in mice exposed to high-fat diet (HFD), injected with streptozotocin, or both in combination (streptozotocin/HFD). In this context, untargeted and targeted metabolomics indicated an intracellular reduction of αKG synthesis in diabetic CMSCs and in the whole heart of HFD mice. This observation was paralleled by a compromised TDG (thymine DNA glycosylase) and TET1 (ten–eleven translocation protein 1) association and function with TET1 relocating out of the nucleus. Molecular dynamics and mutational analyses showed that αKG binds TDG on Arg275 providing an enzymatic allosteric activation. As a consequence, the enzyme significantly increased its capacity to remove G/T nucleotide mismatches or 5-formylcytosine. Accordingly, an exogenous source of αKG restored the DNA demethylation cycle by promoting TDG function, TET1 nuclear localization, and TET/TDG association. TDG inactivation by CRISPR/Cas9 knockout or TET/TDG siRNA knockdown induced 5-formylcytosine accumulation, thus partially mimicking the diabetic epigenetic landscape in cells of nondiabetic origin. The novel compound (S)-2-[(2,6-dichlorobenzoyl)amino]succinic acid (AA6), identified as an inhibitor of αKG dehydrogenase, increased the αKG level in diabetic CMSCs and in the heart of HFD and streptozotocin mice eliciting, in HFD, DNA demethylation, glucose uptake, and insulin response.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Conclusions:</jats:underline> </jats:title> <jats:p>Restoring the epimetabolic control of DNA demethylation cycle promises beneficial effects on cells compromised by environmental metabolic changes.</jats:p> </jats:sec> |
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| spelling | Spallotta, Francesco Cencioni, Chiara Atlante, Sandra Garella, Davide Cocco, Mattia Mori, Mattia Mastrocola, Raffaella Kuenne, Carsten Guenther, Stefan Nanni, Simona Azzimato, Valerio Zukunft, Sven Kornberger, Angela Sürün, Duran Schnütgen, Frank von Melchner, Harald Di Stilo, Antonella Aragno, Manuela Braspenning, Maarten van Criekinge, Wim De Blasio, Miles J. Ritchie, Rebecca H. Zaccagnini, Germana Martelli, Fabio Farsetti, Antonella Fleming, Ingrid Braun, Thomas Beiras-Fernandez, Andres Botta, Bruno Collino, Massimo Bertinaria, Massimo Zeiher, Andreas M. Gaetano, Carlo 0009-7330 1524-4571 Ovid Technologies (Wolters Kluwer Health) Cardiology and Cardiovascular Medicine Physiology http://dx.doi.org/10.1161/circresaha.117.311300 <jats:sec> <jats:title> <jats:underline>Rationale:</jats:underline> </jats:title> <jats:p>Human cardiac mesenchymal cells (CMSCs) are a therapeutically relevant primary cell population. Diabetes mellitus compromises CMSC function as consequence of metabolic alterations and incorporation of stable epigenetic changes.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Objective:</jats:underline> </jats:title> <jats:p>To investigate the role of α-ketoglutarate (αKG) in the epimetabolic control of DNA demethylation in CMSCs.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Methods and Results:</jats:underline> </jats:title> <jats:p>Quantitative global analysis, methylated and hydroxymethylated DNA sequencing, and gene-specific GC methylation detection revealed an accumulation of 5-methylcytosine, 5-hydroxymethylcytosine, and 5-formylcytosine in the genomic DNA of human CMSCs isolated from diabetic donors. Whole heart genomic DNA analysis revealed iterative oxidative cytosine modification accumulation in mice exposed to high-fat diet (HFD), injected with streptozotocin, or both in combination (streptozotocin/HFD). In this context, untargeted and targeted metabolomics indicated an intracellular reduction of αKG synthesis in diabetic CMSCs and in the whole heart of HFD mice. This observation was paralleled by a compromised TDG (thymine DNA glycosylase) and TET1 (ten–eleven translocation protein 1) association and function with TET1 relocating out of the nucleus. Molecular dynamics and mutational analyses showed that αKG binds TDG on Arg275 providing an enzymatic allosteric activation. As a consequence, the enzyme significantly increased its capacity to remove G/T nucleotide mismatches or 5-formylcytosine. Accordingly, an exogenous source of αKG restored the DNA demethylation cycle by promoting TDG function, TET1 nuclear localization, and TET/TDG association. TDG inactivation by CRISPR/Cas9 knockout or TET/TDG siRNA knockdown induced 5-formylcytosine accumulation, thus partially mimicking the diabetic epigenetic landscape in cells of nondiabetic origin. The novel compound (S)-2-[(2,6-dichlorobenzoyl)amino]succinic acid (AA6), identified as an inhibitor of αKG dehydrogenase, increased the αKG level in diabetic CMSCs and in the heart of HFD and streptozotocin mice eliciting, in HFD, DNA demethylation, glucose uptake, and insulin response.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Conclusions:</jats:underline> </jats:title> <jats:p>Restoring the epimetabolic control of DNA demethylation cycle promises beneficial effects on cells compromised by environmental metabolic changes.</jats:p> </jats:sec> Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation Circulation Research |
| spellingShingle | Spallotta, Francesco, Cencioni, Chiara, Atlante, Sandra, Garella, Davide, Cocco, Mattia, Mori, Mattia, Mastrocola, Raffaella, Kuenne, Carsten, Guenther, Stefan, Nanni, Simona, Azzimato, Valerio, Zukunft, Sven, Kornberger, Angela, Sürün, Duran, Schnütgen, Frank, von Melchner, Harald, Di Stilo, Antonella, Aragno, Manuela, Braspenning, Maarten, van Criekinge, Wim, De Blasio, Miles J., Ritchie, Rebecca H., Zaccagnini, Germana, Martelli, Fabio, Farsetti, Antonella, Fleming, Ingrid, Braun, Thomas, Beiras-Fernandez, Andres, Botta, Bruno, Collino, Massimo, Bertinaria, Massimo, Zeiher, Andreas M., Gaetano, Carlo, Circulation Research, Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation, Cardiology and Cardiovascular Medicine, Physiology |
| title | Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation |
| title_full | Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation |
| title_fullStr | Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation |
| title_full_unstemmed | Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation |
| title_short | Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation |
| title_sort | stable oxidative cytosine modifications accumulate in cardiac mesenchymal cells from type2 diabetes patients : rescue by α-ketoglutarate and tet-tdg functional reactivation |
| title_sub | Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation |
| title_unstemmed | Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients : Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation |
| topic | Cardiology and Cardiovascular Medicine, Physiology |
| url | http://dx.doi.org/10.1161/circresaha.117.311300 |