Inward Rectifier K+ Currents Contribute to the Proarrhythmic Electrical Phenotype of Atria Overexpressing Cyclic Adenosine Monophosphate Response Element Modulator Isoform CREM‐IbΔC‐X
BACKGROUND Transgenic mice (TG) with heart‐directed overexpresion of the isoform of the transcription factor cyclic adenosine monophosphate response element modulator (CREM), CREM‐IbΔC‐X, display spontaneous atrial fibrillation (AF) and action potential prolongation. The remodeling of the underlying...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-12-01
|
| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.119.016144 |
| _version_ | 1811332424652554240 |
|---|---|
| author | Florentina Pluteanu Matthias D. Seidl Sabine Hamer Beatrix Scholz Frank U. Müller |
| author_facet | Florentina Pluteanu Matthias D. Seidl Sabine Hamer Beatrix Scholz Frank U. Müller |
| author_sort | Florentina Pluteanu |
| collection | DOAJ |
| description | BACKGROUND Transgenic mice (TG) with heart‐directed overexpresion of the isoform of the transcription factor cyclic adenosine monophosphate response element modulator (CREM), CREM‐IbΔC‐X, display spontaneous atrial fibrillation (AF) and action potential prolongation. The remodeling of the underlying ionic currents remains unknown. Here, we investigated the regulatory role of CREM‐IbΔC‐X on the expression of K+ channel subunits and the corresponding K+ currents in relation to AF onset in TG atrial myocytes. METHODS AND RESULTS ECG recordings documented the absence or presence of AF in 6‐week‐old (before AF onset) and 12‐week‐old TG (after AF onset) and wild‐type littermate mice before atria removal to perform patch clamp, contractility, and biochemical experiments. In TG atrial myocytes, we found reduced repolarization reserve K+ currents attributed to a decrease of transiently outward current and inward rectifier K+ current with phenotype progression, and of acetylcholine‐activated K+ current, age independent. The molecular determinants of these changes were lower mRNA levels of Kcnd2/3, Kcnip2, Kcnj2/4, and Kcnj3/5 and decreased protein levels of K+ channel interacting protein 2 (KChIP2 ), Kir2.1/3, and Kir3.1/4, respectively. After AF onset, inward rectifier K+ current contributed less to action potential repolarization, in line with the absence of outward current component, whereas the acetylcholine‐induced action potential shortening before AF onset (6‐week‐old TG mice) was smaller than in wild‐type and 12‐week‐old TG mice. Atrial force of contraction measured under combined vagal‐sympathetic stimulation revealed increased sensitivity to isoprenaline irrespective of AF onset in TG. Moreover, we identified Kcnd2, Kcnd3, Kcnj3, and Kcnh2 as novel CREM‐target genes. CONCLUSIONS Our study links the activation of cyclic adenosine monophosphate response element–mediated transcription to the proarrhythmogenic electrical remodeling of atrial inward rectifier K+ currents with a role in action potential duration, resting membrane stability, and vagal control of the electrical activity. |
| first_indexed | 2024-04-13T16:35:45Z |
| format | Article |
| id | doaj.art-f5c5423e17954e17af07d2791ae9a1ff |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-13T16:35:45Z |
| publishDate | 2020-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-f5c5423e17954e17af07d2791ae9a1ff2022-12-22T02:39:26ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802020-12-0192310.1161/JAHA.119.016144Inward Rectifier K+ Currents Contribute to the Proarrhythmic Electrical Phenotype of Atria Overexpressing Cyclic Adenosine Monophosphate Response Element Modulator Isoform CREM‐IbΔC‐XFlorentina Pluteanu0Matthias D. Seidl1Sabine Hamer2Beatrix Scholz3Frank U. Müller4Institute of Pharmacology and Toxicology University of Münster Münster GermanyInstitute of Pharmacology and Toxicology University of Münster Münster GermanyInstitute of Pharmacology and Toxicology University of Münster Münster GermanyInstitute of Pharmacology and Toxicology University of Münster Münster GermanyInstitute of Pharmacology and Toxicology University of Münster Münster GermanyBACKGROUND Transgenic mice (TG) with heart‐directed overexpresion of the isoform of the transcription factor cyclic adenosine monophosphate response element modulator (CREM), CREM‐IbΔC‐X, display spontaneous atrial fibrillation (AF) and action potential prolongation. The remodeling of the underlying ionic currents remains unknown. Here, we investigated the regulatory role of CREM‐IbΔC‐X on the expression of K+ channel subunits and the corresponding K+ currents in relation to AF onset in TG atrial myocytes. METHODS AND RESULTS ECG recordings documented the absence or presence of AF in 6‐week‐old (before AF onset) and 12‐week‐old TG (after AF onset) and wild‐type littermate mice before atria removal to perform patch clamp, contractility, and biochemical experiments. In TG atrial myocytes, we found reduced repolarization reserve K+ currents attributed to a decrease of transiently outward current and inward rectifier K+ current with phenotype progression, and of acetylcholine‐activated K+ current, age independent. The molecular determinants of these changes were lower mRNA levels of Kcnd2/3, Kcnip2, Kcnj2/4, and Kcnj3/5 and decreased protein levels of K+ channel interacting protein 2 (KChIP2 ), Kir2.1/3, and Kir3.1/4, respectively. After AF onset, inward rectifier K+ current contributed less to action potential repolarization, in line with the absence of outward current component, whereas the acetylcholine‐induced action potential shortening before AF onset (6‐week‐old TG mice) was smaller than in wild‐type and 12‐week‐old TG mice. Atrial force of contraction measured under combined vagal‐sympathetic stimulation revealed increased sensitivity to isoprenaline irrespective of AF onset in TG. Moreover, we identified Kcnd2, Kcnd3, Kcnj3, and Kcnh2 as novel CREM‐target genes. CONCLUSIONS Our study links the activation of cyclic adenosine monophosphate response element–mediated transcription to the proarrhythmogenic electrical remodeling of atrial inward rectifier K+ currents with a role in action potential duration, resting membrane stability, and vagal control of the electrical activity.https://www.ahajournals.org/doi/10.1161/JAHA.119.016144atrial fibrillationelectrical remodelinginward rectifiersK+ channel |
| spellingShingle | Florentina Pluteanu Matthias D. Seidl Sabine Hamer Beatrix Scholz Frank U. Müller Inward Rectifier K+ Currents Contribute to the Proarrhythmic Electrical Phenotype of Atria Overexpressing Cyclic Adenosine Monophosphate Response Element Modulator Isoform CREM‐IbΔC‐X Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease atrial fibrillation electrical remodeling inward rectifiers K+ channel |
| title | Inward Rectifier K+ Currents Contribute to the Proarrhythmic Electrical Phenotype of Atria Overexpressing Cyclic Adenosine Monophosphate Response Element Modulator Isoform CREM‐IbΔC‐X |
| title_full | Inward Rectifier K+ Currents Contribute to the Proarrhythmic Electrical Phenotype of Atria Overexpressing Cyclic Adenosine Monophosphate Response Element Modulator Isoform CREM‐IbΔC‐X |
| title_fullStr | Inward Rectifier K+ Currents Contribute to the Proarrhythmic Electrical Phenotype of Atria Overexpressing Cyclic Adenosine Monophosphate Response Element Modulator Isoform CREM‐IbΔC‐X |
| title_full_unstemmed | Inward Rectifier K+ Currents Contribute to the Proarrhythmic Electrical Phenotype of Atria Overexpressing Cyclic Adenosine Monophosphate Response Element Modulator Isoform CREM‐IbΔC‐X |
| title_short | Inward Rectifier K+ Currents Contribute to the Proarrhythmic Electrical Phenotype of Atria Overexpressing Cyclic Adenosine Monophosphate Response Element Modulator Isoform CREM‐IbΔC‐X |
| title_sort | inward rectifier k currents contribute to the proarrhythmic electrical phenotype of atria overexpressing cyclic adenosine monophosphate response element modulator isoform crem ibδc x |
| topic | atrial fibrillation electrical remodeling inward rectifiers K+ channel |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.119.016144 |
| work_keys_str_mv | AT florentinapluteanu inwardrectifierkcurrentscontributetotheproarrhythmicelectricalphenotypeofatriaoverexpressingcyclicadenosinemonophosphateresponseelementmodulatorisoformcremibdcx AT matthiasdseidl inwardrectifierkcurrentscontributetotheproarrhythmicelectricalphenotypeofatriaoverexpressingcyclicadenosinemonophosphateresponseelementmodulatorisoformcremibdcx AT sabinehamer inwardrectifierkcurrentscontributetotheproarrhythmicelectricalphenotypeofatriaoverexpressingcyclicadenosinemonophosphateresponseelementmodulatorisoformcremibdcx AT beatrixscholz inwardrectifierkcurrentscontributetotheproarrhythmicelectricalphenotypeofatriaoverexpressingcyclicadenosinemonophosphateresponseelementmodulatorisoformcremibdcx AT frankumuller inwardrectifierkcurrentscontributetotheproarrhythmicelectricalphenotypeofatriaoverexpressingcyclicadenosinemonophosphateresponseelementmodulatorisoformcremibdcx |