NFATc3-dependent loss of Ito gradient across the left ventricular wall during chronic β adrenergic stimulation

Charles F. Rossow, Keith W. Dilly, Can Yuan, Madeline Nieves-Cintrón, Jennifer L. Cabarrus, Luis Fernando Santana

Research output: Contribution to journalArticle

27 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)249-256
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume46
Issue number2
DOIs
StatePublished - Feb 2009
Externally publishedYes

Fingerprint

Adrenergic Agents
Muscle Cells
Calcineurin
Isoproterenol
Heart Ventricles
Adrenergic Agonists
Adrenergic Receptors
Transcription Factors
transcription factor NF-AT c3

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 Fernando.

In: Journal of Molecular and Cellular Cardiology, Vol. 46, No. 2, 02.2009, p. 249-256.

Research output: Contribution to journalArticle

Rossow, Charles F. ; Dilly, Keith W. ; Yuan, Can ; Nieves-Cintrón, Madeline ; Cabarrus, Jennifer L. ; Santana, Luis Fernando. / NFATc3-dependent loss of Ito gradient across the left ventricular wall during chronic β adrenergic stimulation. In: Journal of Molecular and Cellular Cardiology. 2009 ; Vol. 46, No. 2. pp. 249-256.
@article{7bc68bffe67346fd96b4b468f3bd538d,
title = "NFATc3-dependent loss of Ito gradient across the left ventricular wall during chronic β adrenergic stimulation",
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.",
keywords = "Adrenergic signaling, Arrhythmias, Heart failure, Hypertrophy, Kv4.2, Kv4.3",
author = "Rossow, {Charles F.} and Dilly, {Keith W.} and Can Yuan and Madeline Nieves-Cintr{\'o}n and Cabarrus, {Jennifer L.} and Santana, {Luis Fernando}",
year = "2009",
month = "2",
doi = "10.1016/j.yjmcc.2008.10.016",
language = "English (US)",
volume = "46",
pages = "249--256",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Academic Press Inc.",
number = "2",

}

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 Fernando

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

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 -