Cellular and molecular determinants of altered Ca2+ handling in the failing rabbit heart: Primary defects in SR Ca2+ uptake and release mechanisms

Antonis A. Armoundas, Jochen Rose, Rajesh Aggarwal, Bruno D. Stuyvers, Brian O'Rourke, David A. Kass, Eduardo Marbán, Stephen R. Shorofsky, Gordon F. Tomaselli, C. William Balke

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Myocytes from the failing myocardium exhibit depressed and prolonged intracellular Ca2+ concentration ([Ca2+]i) transients that are, in part, responsible for contractile dysfunction and unstable repolarization. To better understand the molecular basis of the aberrant Ca2+ handling in heart failure (HF), we studied the rabbit pacing tachycardia HF model. Induction of HF was associated with action potential (AP) duration prolongation that was especially pronounced at low stimulation frequencies. L-type calcium channel current (ICa,L) density (-0.964 ± 0.172 vs. -0.745 ± 0.128 pA/pF at +10 mV) and Na+/Ca2+ exchanger (NCX) currents (2.1 ± 0.8 vs. 2.3 ± 0.8 pA/pF at +30 mV) were not different in myocytes from control and failing hearts. The amplitude of peak [Ca2+]i was depressed (at +10 mV, 0.72 ± 0.07 and 0.56 ± 0.04 μM in normal and failing hearts, respectively; P < 0.05), with slowed rates of decay and reduced Ca2+ spark amplitudes (P < 0.0001) in myocytes isolated from failing vs. control hearts. Inhibition of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a revealed a greater reliance on NCX to remove cytosolic Ca2+ in myocytes isolated from failing vs. control hearts (P < 0.05). mRNA levels of the -α1C-subunit, ryanodine receptor (RyR), and NCX were unchanged from controls, while SERCA2a and phospholamban (PLB) were significantly downregulated in failing vs. control hearts (P < 0.05). -α1C protein levels were unchanged, RyR, SERCA2a, and PLB were significantly downregulated (P < 0.05), while NCX protein was significantly upregulated (P < 0.05). These results support a prominent role for the sarcoplasmic reticulum (SR) in the pathogenesis of HF, in which abnormal SR Ca2+ uptake and release synergistically contribute to the depressed [Ca2+]i and the altered AP profile phenotype.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume292
Issue number3
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

Fingerprint

Sarcoplasmic Reticulum
Muscle Cells
Rabbits
Heart Failure
Ryanodine Receptor Calcium Release Channel
Action Potentials
Down-Regulation
L-Type Calcium Channels
Reticulum
Calcium-Transporting ATPases
Tachycardia
Myocardium
Proteins
Phenotype
Messenger RNA
phospholamban

Keywords

  • Calcium
  • Ion channels
  • Pacing tachycardia
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Cellular and molecular determinants of altered Ca2+ handling in the failing rabbit heart : Primary defects in SR Ca2+ uptake and release mechanisms. / Armoundas, Antonis A.; Rose, Jochen; Aggarwal, Rajesh; Stuyvers, Bruno D.; O'Rourke, Brian; Kass, David A.; Marbán, Eduardo; Shorofsky, Stephen R.; Tomaselli, Gordon F.; Balke, C. William.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 292, No. 3, 01.03.2007.

Research output: Contribution to journalArticle

Armoundas, Antonis A. ; Rose, Jochen ; Aggarwal, Rajesh ; Stuyvers, Bruno D. ; O'Rourke, Brian ; Kass, David A. ; Marbán, Eduardo ; Shorofsky, Stephen R. ; Tomaselli, Gordon F. ; Balke, C. William. / Cellular and molecular determinants of altered Ca2+ handling in the failing rabbit heart : Primary defects in SR Ca2+ uptake and release mechanisms. In: American Journal of Physiology - Heart and Circulatory Physiology. 2007 ; Vol. 292, No. 3.
@article{e4c07128fba145409ae0191fbaa489e4,
title = "Cellular and molecular determinants of altered Ca2+ handling in the failing rabbit heart: Primary defects in SR Ca2+ uptake and release mechanisms",
abstract = "Myocytes from the failing myocardium exhibit depressed and prolonged intracellular Ca2+ concentration ([Ca2+]i) transients that are, in part, responsible for contractile dysfunction and unstable repolarization. To better understand the molecular basis of the aberrant Ca2+ handling in heart failure (HF), we studied the rabbit pacing tachycardia HF model. Induction of HF was associated with action potential (AP) duration prolongation that was especially pronounced at low stimulation frequencies. L-type calcium channel current (ICa,L) density (-0.964 ± 0.172 vs. -0.745 ± 0.128 pA/pF at +10 mV) and Na+/Ca2+ exchanger (NCX) currents (2.1 ± 0.8 vs. 2.3 ± 0.8 pA/pF at +30 mV) were not different in myocytes from control and failing hearts. The amplitude of peak [Ca2+]i was depressed (at +10 mV, 0.72 ± 0.07 and 0.56 ± 0.04 μM in normal and failing hearts, respectively; P < 0.05), with slowed rates of decay and reduced Ca2+ spark amplitudes (P < 0.0001) in myocytes isolated from failing vs. control hearts. Inhibition of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a revealed a greater reliance on NCX to remove cytosolic Ca2+ in myocytes isolated from failing vs. control hearts (P < 0.05). mRNA levels of the -α1C-subunit, ryanodine receptor (RyR), and NCX were unchanged from controls, while SERCA2a and phospholamban (PLB) were significantly downregulated in failing vs. control hearts (P < 0.05). -α1C protein levels were unchanged, RyR, SERCA2a, and PLB were significantly downregulated (P < 0.05), while NCX protein was significantly upregulated (P < 0.05). These results support a prominent role for the sarcoplasmic reticulum (SR) in the pathogenesis of HF, in which abnormal SR Ca2+ uptake and release synergistically contribute to the depressed [Ca2+]i and the altered AP profile phenotype.",
keywords = "Calcium, Ion channels, Pacing tachycardia, Sarcoplasmic reticulum",
author = "Armoundas, {Antonis A.} and Jochen Rose and Rajesh Aggarwal and Stuyvers, {Bruno D.} and Brian O'Rourke and Kass, {David A.} and Eduardo Marb{\'a}n and Shorofsky, {Stephen R.} and Tomaselli, {Gordon F.} and Balke, {C. William}",
year = "2007",
month = "3",
day = "1",
doi = "10.1152/ajpheart.00525.2006",
language = "English (US)",
volume = "292",
journal = "American Journal of Physiology - Renal Fluid and Electrolyte Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "3",

}

TY - JOUR

T1 - Cellular and molecular determinants of altered Ca2+ handling in the failing rabbit heart

T2 - Primary defects in SR Ca2+ uptake and release mechanisms

AU - Armoundas, Antonis A.

AU - Rose, Jochen

AU - Aggarwal, Rajesh

AU - Stuyvers, Bruno D.

AU - O'Rourke, Brian

AU - Kass, David A.

AU - Marbán, Eduardo

AU - Shorofsky, Stephen R.

AU - Tomaselli, Gordon F.

AU - Balke, C. William

PY - 2007/3/1

Y1 - 2007/3/1

N2 - Myocytes from the failing myocardium exhibit depressed and prolonged intracellular Ca2+ concentration ([Ca2+]i) transients that are, in part, responsible for contractile dysfunction and unstable repolarization. To better understand the molecular basis of the aberrant Ca2+ handling in heart failure (HF), we studied the rabbit pacing tachycardia HF model. Induction of HF was associated with action potential (AP) duration prolongation that was especially pronounced at low stimulation frequencies. L-type calcium channel current (ICa,L) density (-0.964 ± 0.172 vs. -0.745 ± 0.128 pA/pF at +10 mV) and Na+/Ca2+ exchanger (NCX) currents (2.1 ± 0.8 vs. 2.3 ± 0.8 pA/pF at +30 mV) were not different in myocytes from control and failing hearts. The amplitude of peak [Ca2+]i was depressed (at +10 mV, 0.72 ± 0.07 and 0.56 ± 0.04 μM in normal and failing hearts, respectively; P < 0.05), with slowed rates of decay and reduced Ca2+ spark amplitudes (P < 0.0001) in myocytes isolated from failing vs. control hearts. Inhibition of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a revealed a greater reliance on NCX to remove cytosolic Ca2+ in myocytes isolated from failing vs. control hearts (P < 0.05). mRNA levels of the -α1C-subunit, ryanodine receptor (RyR), and NCX were unchanged from controls, while SERCA2a and phospholamban (PLB) were significantly downregulated in failing vs. control hearts (P < 0.05). -α1C protein levels were unchanged, RyR, SERCA2a, and PLB were significantly downregulated (P < 0.05), while NCX protein was significantly upregulated (P < 0.05). These results support a prominent role for the sarcoplasmic reticulum (SR) in the pathogenesis of HF, in which abnormal SR Ca2+ uptake and release synergistically contribute to the depressed [Ca2+]i and the altered AP profile phenotype.

AB - Myocytes from the failing myocardium exhibit depressed and prolonged intracellular Ca2+ concentration ([Ca2+]i) transients that are, in part, responsible for contractile dysfunction and unstable repolarization. To better understand the molecular basis of the aberrant Ca2+ handling in heart failure (HF), we studied the rabbit pacing tachycardia HF model. Induction of HF was associated with action potential (AP) duration prolongation that was especially pronounced at low stimulation frequencies. L-type calcium channel current (ICa,L) density (-0.964 ± 0.172 vs. -0.745 ± 0.128 pA/pF at +10 mV) and Na+/Ca2+ exchanger (NCX) currents (2.1 ± 0.8 vs. 2.3 ± 0.8 pA/pF at +30 mV) were not different in myocytes from control and failing hearts. The amplitude of peak [Ca2+]i was depressed (at +10 mV, 0.72 ± 0.07 and 0.56 ± 0.04 μM in normal and failing hearts, respectively; P < 0.05), with slowed rates of decay and reduced Ca2+ spark amplitudes (P < 0.0001) in myocytes isolated from failing vs. control hearts. Inhibition of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a revealed a greater reliance on NCX to remove cytosolic Ca2+ in myocytes isolated from failing vs. control hearts (P < 0.05). mRNA levels of the -α1C-subunit, ryanodine receptor (RyR), and NCX were unchanged from controls, while SERCA2a and phospholamban (PLB) were significantly downregulated in failing vs. control hearts (P < 0.05). -α1C protein levels were unchanged, RyR, SERCA2a, and PLB were significantly downregulated (P < 0.05), while NCX protein was significantly upregulated (P < 0.05). These results support a prominent role for the sarcoplasmic reticulum (SR) in the pathogenesis of HF, in which abnormal SR Ca2+ uptake and release synergistically contribute to the depressed [Ca2+]i and the altered AP profile phenotype.

KW - Calcium

KW - Ion channels

KW - Pacing tachycardia

KW - Sarcoplasmic reticulum

UR - http://www.scopus.com/inward/record.url?scp=33847748590&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33847748590&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00525.2006

DO - 10.1152/ajpheart.00525.2006

M3 - Article

C2 - 17122195

AN - SCOPUS:33847748590

VL - 292

JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

SN - 1931-857X

IS - 3

ER -