Small Conductance Ca2 +-Activated K+ (SK) Channel mRNA Expression in Human Atrial and Ventricular Tissue: Comparison Between Donor, Atrial Fibrillation and Heart Failure Tissue
In search of more efficacious and safe pharmacological treatments for atrial fibrillation (AF), atria-selective antiarrhythmic agents have been promoted that target ion channels principally expressed in the atria. This concept allows one to engage antiarrhythmic effects in atria, but spares the vent...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-04-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2021.650964/full |
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| author | Elisa Darkow Elisa Darkow Elisa Darkow Elisa Darkow Thong T. Nguyen Marina Stolina Fabian A. Kari Fabian A. Kari Constanze Schmidt Constanze Schmidt Felix Wiedmann Felix Wiedmann István Baczkó Peter Kohl Peter Kohl Peter Kohl Sridharan Rajamani Ursula Ravens Ursula Ravens Rémi Peyronnet Rémi Peyronnet |
| author_facet | Elisa Darkow Elisa Darkow Elisa Darkow Elisa Darkow Thong T. Nguyen Marina Stolina Fabian A. Kari Fabian A. Kari Constanze Schmidt Constanze Schmidt Felix Wiedmann Felix Wiedmann István Baczkó Peter Kohl Peter Kohl Peter Kohl Sridharan Rajamani Ursula Ravens Ursula Ravens Rémi Peyronnet Rémi Peyronnet |
| author_sort | Elisa Darkow |
| collection | DOAJ |
| description | In search of more efficacious and safe pharmacological treatments for atrial fibrillation (AF), atria-selective antiarrhythmic agents have been promoted that target ion channels principally expressed in the atria. This concept allows one to engage antiarrhythmic effects in atria, but spares the ventricles from potentially proarrhythmic side effects. It has been suggested that cardiac small conductance Ca2+-activated K+ (SK) channels may represent an atria-selective target in mammals including humans. However, there are conflicting data concerning the expression of SK channels in different stages of AF, and recent findings suggest that SK channels are upregulated in ventricular myocardium when patients develop heart failure. To address this issue, RNA-sequencing was performed to compare expression levels of three SK channels (KCNN1, KCNN2, and KCNN3) in human atrial and ventricular tissue samples from transplant donor hearts (no cardiac disease), and patients with cardiac disease in sinus rhythm or with AF. In addition, for control purposes expression levels of several genes known to be either chamber-selective or differentially expressed in AF and heart failure were determined. In atria, as compared to ventricle from transplant donor hearts, we confirmed higher expression of KCNN1 and KCNA5, and lower expression of KCNJ2, whereas KCNN2 and KCNN3 were statistically not differentially expressed. Overall expression of KCNN1 was low compared to KCNN2 and KCNN3. Comparing atrial tissue from patients with AF to sinus rhythm samples we saw downregulation of KCNN2 in AF, as previously reported. When comparing ventricular tissue from heart failure patients to non-diseased samples, we found significantly increased ventricular expression of KCNN3 in heart failure, as previously published. The other channels showed no significant difference in expression in either disease. Our results add weight to the view that SK channels are not likely to be an atria-selective target, especially in failing human hearts, and modulators of these channels may prove to have less utility in treating AF than hoped. Whether targeting SK1 holds potential remains to be elucidated. |
| first_indexed | 2024-12-16T20:42:39Z |
| format | Article |
| id | doaj.art-ddf44bced1ca4c75b664065aa511da6e |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-16T20:42:39Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Physiology |
| spelling | doaj.art-ddf44bced1ca4c75b664065aa511da6e2022-12-21T22:17:01ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2021-04-011210.3389/fphys.2021.650964650964Small Conductance Ca2 +-Activated K+ (SK) Channel mRNA Expression in Human Atrial and Ventricular Tissue: Comparison Between Donor, Atrial Fibrillation and Heart Failure TissueElisa Darkow0Elisa Darkow1Elisa Darkow2Elisa Darkow3Thong T. Nguyen4Marina Stolina5Fabian A. Kari6Fabian A. Kari7Constanze Schmidt8Constanze Schmidt9Felix Wiedmann10Felix Wiedmann11István Baczkó12Peter Kohl13Peter Kohl14Peter Kohl15Sridharan Rajamani16Ursula Ravens17Ursula Ravens18Rémi Peyronnet19Rémi Peyronnet20Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg-Bad Krozingen, Freiburg im Breisgau, GermanyMedical Center and Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, GermanySpemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg im Breisgau, GermanyFaculty of Biology, University of Freiburg, Freiburg im Breisgau, GermanyGenome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA, United StatesDepartment of Cardiometabolic Disorders, Amgen Research, Amgen Inc., Thousand Oaks, CA, United StatesMedical Center and Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, GermanyDepartment of Cardiovascular Surgery, University Heart Center Freiburg-Bad Krozingen, Freiburg im Breisgau, GermanyDepartment of Cardiology, University Hospital Heidelberg, Heidelberg, GermanyDZHK (German Center for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Heidelberg University, Heidelberg, GermanyDepartment of Cardiology, University Hospital Heidelberg, Heidelberg, GermanyDZHK (German Center for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Heidelberg University, Heidelberg, Germany0Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, HungaryInstitute for Experimental Cardiovascular Medicine, University Heart Center Freiburg-Bad Krozingen, Freiburg im Breisgau, GermanyMedical Center and Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany1CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg im Breisgau, Germany2Translational Safety and Bioanalytical Sciences, Amgen Research, Amgen Inc., South San Francisco, CA, United StatesInstitute for Experimental Cardiovascular Medicine, University Heart Center Freiburg-Bad Krozingen, Freiburg im Breisgau, GermanyMedical Center and Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, GermanyInstitute for Experimental Cardiovascular Medicine, University Heart Center Freiburg-Bad Krozingen, Freiburg im Breisgau, GermanyMedical Center and Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, GermanyIn search of more efficacious and safe pharmacological treatments for atrial fibrillation (AF), atria-selective antiarrhythmic agents have been promoted that target ion channels principally expressed in the atria. This concept allows one to engage antiarrhythmic effects in atria, but spares the ventricles from potentially proarrhythmic side effects. It has been suggested that cardiac small conductance Ca2+-activated K+ (SK) channels may represent an atria-selective target in mammals including humans. However, there are conflicting data concerning the expression of SK channels in different stages of AF, and recent findings suggest that SK channels are upregulated in ventricular myocardium when patients develop heart failure. To address this issue, RNA-sequencing was performed to compare expression levels of three SK channels (KCNN1, KCNN2, and KCNN3) in human atrial and ventricular tissue samples from transplant donor hearts (no cardiac disease), and patients with cardiac disease in sinus rhythm or with AF. In addition, for control purposes expression levels of several genes known to be either chamber-selective or differentially expressed in AF and heart failure were determined. In atria, as compared to ventricle from transplant donor hearts, we confirmed higher expression of KCNN1 and KCNA5, and lower expression of KCNJ2, whereas KCNN2 and KCNN3 were statistically not differentially expressed. Overall expression of KCNN1 was low compared to KCNN2 and KCNN3. Comparing atrial tissue from patients with AF to sinus rhythm samples we saw downregulation of KCNN2 in AF, as previously reported. When comparing ventricular tissue from heart failure patients to non-diseased samples, we found significantly increased ventricular expression of KCNN3 in heart failure, as previously published. The other channels showed no significant difference in expression in either disease. Our results add weight to the view that SK channels are not likely to be an atria-selective target, especially in failing human hearts, and modulators of these channels may prove to have less utility in treating AF than hoped. Whether targeting SK1 holds potential remains to be elucidated.https://www.frontiersin.org/articles/10.3389/fphys.2021.650964/fullRNA-seqSK channelsAF marker genesatria-selective drugsatrial fibrillation |
| spellingShingle | Elisa Darkow Elisa Darkow Elisa Darkow Elisa Darkow Thong T. Nguyen Marina Stolina Fabian A. Kari Fabian A. Kari Constanze Schmidt Constanze Schmidt Felix Wiedmann Felix Wiedmann István Baczkó Peter Kohl Peter Kohl Peter Kohl Sridharan Rajamani Ursula Ravens Ursula Ravens Rémi Peyronnet Rémi Peyronnet Small Conductance Ca2 +-Activated K+ (SK) Channel mRNA Expression in Human Atrial and Ventricular Tissue: Comparison Between Donor, Atrial Fibrillation and Heart Failure Tissue Frontiers in Physiology RNA-seq SK channels AF marker genes atria-selective drugs atrial fibrillation |
| title | Small Conductance Ca2 +-Activated K+ (SK) Channel mRNA Expression in Human Atrial and Ventricular Tissue: Comparison Between Donor, Atrial Fibrillation and Heart Failure Tissue |
| title_full | Small Conductance Ca2 +-Activated K+ (SK) Channel mRNA Expression in Human Atrial and Ventricular Tissue: Comparison Between Donor, Atrial Fibrillation and Heart Failure Tissue |
| title_fullStr | Small Conductance Ca2 +-Activated K+ (SK) Channel mRNA Expression in Human Atrial and Ventricular Tissue: Comparison Between Donor, Atrial Fibrillation and Heart Failure Tissue |
| title_full_unstemmed | Small Conductance Ca2 +-Activated K+ (SK) Channel mRNA Expression in Human Atrial and Ventricular Tissue: Comparison Between Donor, Atrial Fibrillation and Heart Failure Tissue |
| title_short | Small Conductance Ca2 +-Activated K+ (SK) Channel mRNA Expression in Human Atrial and Ventricular Tissue: Comparison Between Donor, Atrial Fibrillation and Heart Failure Tissue |
| title_sort | small conductance ca2 activated k sk channel mrna expression in human atrial and ventricular tissue comparison between donor atrial fibrillation and heart failure tissue |
| topic | RNA-seq SK channels AF marker genes atria-selective drugs atrial fibrillation |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2021.650964/full |
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