Abstract
In heart, pore-forming Kv4 α channel subunits underlie the K+ transient outward current (Ito). Expression of Kv4 is greater in left ventricular epicardial (EPI) than in endocardial (ENDO) cells, resulting in larger Ito in EPI than in ENDO cells. In adult ventricular myocytes, the transcription factor NFATc3 suppresses Kv4 expression. NFATc3 activity is higher in ENDO than in EPI cells and this has been proposed to contribute to heterogeneous Kv4 expression across the left ventricular free wall. Here, we tested the hypothesis that regional activation of NFATc3 signaling dissipates the gradient of Ito density across the mouse left ventricle during chronic activation of β adrenergic signaling. [Ca2+]i, calcineurin, and NFAT activity were larger in ENDO than in EPI myocytes. Infusion of the β adrenergic receptor agonist isoproterenol increased [Ca2+]i, calcineurin, and NFAT activity in EPI, but not in ENDO myocytes, leading to equalization of these parameters in EPI and ENDO cells. This was accompanied by dissipation of the transmural gradient in Kv4.2 expression and Ito density. Unlike wild type, ENDO or EPI myocytes from β1 adrenergic receptor-null and NFATc3-null mice did not undergo changes in Ito density during isoproterenol infusion. Collectively, these data suggest that calcineurin and NFATc3 signaling contributes to the loss of heterogeneous Kv4 expression, and hence Ito density, in the mouse left ventricle during chronic β adrenergic stimulation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 249-256 |
| Number of pages | 8 |
| Journal | Journal of Molecular and Cellular Cardiology |
| Volume | 46 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2009 |
| Externally published | Yes |
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Keywords
- Adrenergic signaling
- Arrhythmias
- Heart failure
- Hypertrophy
- Kv4.2
- Kv4.3
ASJC Scopus subject areas
- Molecular Biology
- Cardiology and Cardiovascular Medicine
Cite this
NFATc3-dependent loss of Ito gradient across the left ventricular wall during chronic β adrenergic stimulation. / Rossow, Charles F.; Dilly, Keith W.; Yuan, Can; Nieves-Cintrón, Madeline; Cabarrus, Jennifer L.; Santana, Luis F.
In: Journal of Molecular and Cellular Cardiology, Vol. 46, No. 2, 02.2009, p. 249-256.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - NFATc3-dependent loss of Ito gradient across the left ventricular wall during chronic β adrenergic stimulation
AU - Rossow, Charles F.
AU - Dilly, Keith W.
AU - Yuan, Can
AU - Nieves-Cintrón, Madeline
AU - Cabarrus, Jennifer L.
AU - Santana, Luis F.
PY - 2009/2
Y1 - 2009/2
N2 - In heart, pore-forming Kv4 α channel subunits underlie the K+ transient outward current (Ito). Expression of Kv4 is greater in left ventricular epicardial (EPI) than in endocardial (ENDO) cells, resulting in larger Ito in EPI than in ENDO cells. In adult ventricular myocytes, the transcription factor NFATc3 suppresses Kv4 expression. NFATc3 activity is higher in ENDO than in EPI cells and this has been proposed to contribute to heterogeneous Kv4 expression across the left ventricular free wall. Here, we tested the hypothesis that regional activation of NFATc3 signaling dissipates the gradient of Ito density across the mouse left ventricle during chronic activation of β adrenergic signaling. [Ca2+]i, calcineurin, and NFAT activity were larger in ENDO than in EPI myocytes. Infusion of the β adrenergic receptor agonist isoproterenol increased [Ca2+]i, calcineurin, and NFAT activity in EPI, but not in ENDO myocytes, leading to equalization of these parameters in EPI and ENDO cells. This was accompanied by dissipation of the transmural gradient in Kv4.2 expression and Ito density. Unlike wild type, ENDO or EPI myocytes from β1 adrenergic receptor-null and NFATc3-null mice did not undergo changes in Ito density during isoproterenol infusion. Collectively, these data suggest that calcineurin and NFATc3 signaling contributes to the loss of heterogeneous Kv4 expression, and hence Ito density, in the mouse left ventricle during chronic β adrenergic stimulation.
AB - In heart, pore-forming Kv4 α channel subunits underlie the K+ transient outward current (Ito). Expression of Kv4 is greater in left ventricular epicardial (EPI) than in endocardial (ENDO) cells, resulting in larger Ito in EPI than in ENDO cells. In adult ventricular myocytes, the transcription factor NFATc3 suppresses Kv4 expression. NFATc3 activity is higher in ENDO than in EPI cells and this has been proposed to contribute to heterogeneous Kv4 expression across the left ventricular free wall. Here, we tested the hypothesis that regional activation of NFATc3 signaling dissipates the gradient of Ito density across the mouse left ventricle during chronic activation of β adrenergic signaling. [Ca2+]i, calcineurin, and NFAT activity were larger in ENDO than in EPI myocytes. Infusion of the β adrenergic receptor agonist isoproterenol increased [Ca2+]i, calcineurin, and NFAT activity in EPI, but not in ENDO myocytes, leading to equalization of these parameters in EPI and ENDO cells. This was accompanied by dissipation of the transmural gradient in Kv4.2 expression and Ito density. Unlike wild type, ENDO or EPI myocytes from β1 adrenergic receptor-null and NFATc3-null mice did not undergo changes in Ito density during isoproterenol infusion. Collectively, these data suggest that calcineurin and NFATc3 signaling contributes to the loss of heterogeneous Kv4 expression, and hence Ito density, in the mouse left ventricle during chronic β adrenergic stimulation.
KW - Adrenergic signaling
KW - Arrhythmias
KW - Heart failure
KW - Hypertrophy
KW - Kv4.2
KW - Kv4.3
UR - http://www.scopus.com/inward/record.url?scp=58149295972&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=58149295972&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2008.10.016
DO - 10.1016/j.yjmcc.2008.10.016
M3 - Article
C2 - 19027024
AN - SCOPUS:58149295972
VL - 46
SP - 249
EP - 256
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
IS - 2
ER -