Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes
© 2018 The Author(s). Published by S. Karger AG, Basel..
BACKGROUND/AIMS: Cardiac arrhythmias are triggered by environmental stimuli that may modulate expression of cardiac ion channels. Underlying epigenetic regulation of cardiac electrophysiology remains incompletely understood. Histone deacetylases (HDACs) control gene expression and cardiac integrity. We hypothesized that class I/II HDACs transcriptionally regulate ion channel expression and determine action potential duration (APD) in cardiac myocytes.
METHODS: Global class I/II HDAC inhibition was achieved by administration of trichostatin A (TSA). HDAC-mediated effects on K+ channel expression and electrophysiological function were evaluated in murine atrial cardiomyocytes (HL-1 cells) using real-time PCR, Western blot, and patch clamp analyses. Electrical tachypacing was employed to recapitulate arrhythmia-related effects on ion channel remodeling in the absence and presence of HDAC inhibition.
RESULTS: Global HDAC inhibition increased histone acetylation and prolonged APD90 in atrial cardiomyocytes compared to untreated control cells. Transcript levels of voltage-gated or inwardly rectifying K+ channels Kcnq1, Kcnj3 and Kcnj5 were significantly reduced, whereas Kcnk2, Kcnj2 and Kcnd3 mRNAs were upregulated. Ion channel remodeling was similarly observed at protein level. Short-term tachypacing did not induce significant transcriptional K+ channel remodeling.
CONCLUSION: The present findings link class I/II HDAC activity to regulation of ion channel expression and action potential duration in atrial cardiomyocytes. Clinical implications for HDAC-based antiarrhythmic therapy and cardiac safety of HDAC inhibitors require further investigation.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2018 |
|---|---|
| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:49 |
|---|---|
| Enthalten in: |
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology - 49(2018), 1 vom: 30., Seite 65-77 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Lugenbiel, Patrick [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 18.09.2018 Date Revised 12.02.2019 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1159/000492840 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM287726010 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM287726010 | ||
| 003 | DE-627 | ||
| 005 | 20231225054648.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2018 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1159/000492840 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0959.xml |
| 035 | |a (DE-627)NLM287726010 | ||
| 035 | |a (NLM)30134221 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Lugenbiel, Patrick |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes |
| 264 | 1 | |c 2018 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 18.09.2018 | ||
| 500 | |a Date Revised 12.02.2019 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2018 The Author(s). Published by S. Karger AG, Basel. | ||
| 520 | |a BACKGROUND/AIMS: Cardiac arrhythmias are triggered by environmental stimuli that may modulate expression of cardiac ion channels. Underlying epigenetic regulation of cardiac electrophysiology remains incompletely understood. Histone deacetylases (HDACs) control gene expression and cardiac integrity. We hypothesized that class I/II HDACs transcriptionally regulate ion channel expression and determine action potential duration (APD) in cardiac myocytes | ||
| 520 | |a METHODS: Global class I/II HDAC inhibition was achieved by administration of trichostatin A (TSA). HDAC-mediated effects on K+ channel expression and electrophysiological function were evaluated in murine atrial cardiomyocytes (HL-1 cells) using real-time PCR, Western blot, and patch clamp analyses. Electrical tachypacing was employed to recapitulate arrhythmia-related effects on ion channel remodeling in the absence and presence of HDAC inhibition | ||
| 520 | |a RESULTS: Global HDAC inhibition increased histone acetylation and prolonged APD90 in atrial cardiomyocytes compared to untreated control cells. Transcript levels of voltage-gated or inwardly rectifying K+ channels Kcnq1, Kcnj3 and Kcnj5 were significantly reduced, whereas Kcnk2, Kcnj2 and Kcnd3 mRNAs were upregulated. Ion channel remodeling was similarly observed at protein level. Short-term tachypacing did not induce significant transcriptional K+ channel remodeling | ||
| 520 | |a CONCLUSION: The present findings link class I/II HDAC activity to regulation of ion channel expression and action potential duration in atrial cardiomyocytes. Clinical implications for HDAC-based antiarrhythmic therapy and cardiac safety of HDAC inhibitors require further investigation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Atrial fibrillation | |
| 650 | 4 | |a Cardiac action potential | |
| 650 | 4 | |a Epigenetic regulation | |
| 650 | 4 | |a Histone deacetylase | |
| 650 | 4 | |a Ion channel | |
| 650 | 4 | |a Potassium channel | |
| 650 | 4 | |a Tachypacing | |
| 650 | 4 | |a Trichostatin A | |
| 650 | 7 | |a G Protein-Coupled Inwardly-Rectifying Potassium Channels |2 NLM | |
| 650 | 7 | |a Histone Deacetylase Inhibitors |2 NLM | |
| 650 | 7 | |a Hydroxamic Acids |2 NLM | |
| 650 | 7 | |a Potassium Channels |2 NLM | |
| 650 | 7 | |a Potassium Channels, Tandem Pore Domain |2 NLM | |
| 650 | 7 | |a trichostatin A |2 NLM | |
| 650 | 7 | |a 3X2S926L3Z |2 NLM | |
| 650 | 7 | |a Histone Deacetylases |2 NLM | |
| 650 | 7 | |a EC 3.5.1.98 |2 NLM | |
| 700 | 1 | |a Govorov, Katharina |e verfasserin |4 aut | |
| 700 | 1 | |a Rahm, Ann-Kathrin |e verfasserin |4 aut | |
| 700 | 1 | |a Wieder, Teresa |e verfasserin |4 aut | |
| 700 | 1 | |a Gramlich, Dominik |e verfasserin |4 aut | |
| 700 | 1 | |a Syren, Pascal |e verfasserin |4 aut | |
| 700 | 1 | |a Weiberg, Nadine |e verfasserin |4 aut | |
| 700 | 1 | |a Seyler, Claudia |e verfasserin |4 aut | |
| 700 | 1 | |a Katus, Hugo A |e verfasserin |4 aut | |
| 700 | 1 | |a Thomas, Dierk |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology |d 1996 |g 49(2018), 1 vom: 30., Seite 65-77 |w (DE-627)NLM090692519 |x 1421-9778 |7 nnns |
| 773 | 1 | 8 | |g volume:49 |g year:2018 |g number:1 |g day:30 |g pages:65-77 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1159/000492840 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 49 |j 2018 |e 1 |b 30 |h 65-77 | ||