Remodelling of ionic currents in hypertrophied and failing hearts of transgenic mice overexpressing calsequestrin

Björn C. Knollmann, Barbara E C Knollmann-Ritschel, Neil J. Weissman, Larry Jones, Martin Morad

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Abstract

1. Overexpression of cardiac calsequestrin (CSQ) impairs Ca2+ signalling in murine myocytes, leading to marked cardiac hypertrophy. Here we report on contractile, histological and electrophysiological changes accompanying the development of cardiac hypertrophy and failure in CSQ-overexpressing mice. 2. CSQ mice developed contractile dysfunction after 60 days of age, with only 40% survival at 6 months. Four- to 6-month-old CSQ mice revealed biventricular dilatation, cardiomyocyte hypertrophy, patchy interstitial fibrosis and tissue calcifications. 3. Cardiac hypertrophy of CSQ mice was accompanied by progressive P-R and Q-T interval prolongation, conduction blocks, 2-fold prolongation of the ventricular action potential and increased cellular membrane capacitance. 4. Remodelling of ionic currents included marked reduction of both density and absolute magnitude of transient outward (I(to)) and inward rectifying (I(K1)) K+ currents. The density, but not the absolute magnitude, of basal and isoproterenol (isoprenaline)-stimulated Ca2+ current (I(Ca)) was decreased by 42% and the inactivation kinetics of I(Ca) were significantly slowed. Na+ current density was suppressed by 50%, but its steady-state activation and inactivation were shifted to more positive potentials. The density of Na+-Ca2+ exchange current was increased by 35%. 5. In CSQ but not in control myocytes dialysed with cAMP, isoproterenol continued to enhance I(Ca). This apparent lower responsiveness of I(Ca) to cAMP could be reversed by the nonhydrolysable cAMP analogue 8-Br-cAMP or the phosphodiesterase inhibitor IBMX, suggesting high phosphodiesterase activity of CSQ myocytes. 6. In young CSQ mice (< 60 days) with compensated cardiac hypertrophy, only I(to) was significantly suppressed. All other currents remained relatively intact. 7. An increase in cardiac Ca2+-storage capability by overexpression of CSQ results in a dilated cardiomyopathy with tissue fibrosis, calcifications, impaired β-adrenergic signalling and progressive remodelling of ionic currents. The extent of the changes in ionic currents was age dependent.

Original languageEnglish
Pages (from-to)483-498
Number of pages16
JournalJournal of Physiology
Volume525
Issue number2
StatePublished - Jun 1 2000

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Calsequestrin
Transgenic Mice
Cardiomegaly
Isoproterenol
Muscle Cells
Fibrosis
1-Methyl-3-isobutylxanthine
Phosphodiesterase Inhibitors
Phosphoric Diester Hydrolases
Dilated Cardiomyopathy
Cardiac Myocytes
Adrenergic Agents
Hypertrophy
Action Potentials
Dilatation
Heart Failure

ASJC Scopus subject areas

  • Physiology

Cite this

Knollmann, B. C., Knollmann-Ritschel, B. E. C., Weissman, N. J., Jones, L., & Morad, M. (2000). Remodelling of ionic currents in hypertrophied and failing hearts of transgenic mice overexpressing calsequestrin. Journal of Physiology, 525(2), 483-498.

Remodelling of ionic currents in hypertrophied and failing hearts of transgenic mice overexpressing calsequestrin. / Knollmann, Björn C.; Knollmann-Ritschel, Barbara E C; Weissman, Neil J.; Jones, Larry; Morad, Martin.

In: Journal of Physiology, Vol. 525, No. 2, 01.06.2000, p. 483-498.

Research output: Contribution to journalArticle

Knollmann, BC, Knollmann-Ritschel, BEC, Weissman, NJ, Jones, L & Morad, M 2000, 'Remodelling of ionic currents in hypertrophied and failing hearts of transgenic mice overexpressing calsequestrin', Journal of Physiology, vol. 525, no. 2, pp. 483-498.
Knollmann, Björn C. ; Knollmann-Ritschel, Barbara E C ; Weissman, Neil J. ; Jones, Larry ; Morad, Martin. / Remodelling of ionic currents in hypertrophied and failing hearts of transgenic mice overexpressing calsequestrin. In: Journal of Physiology. 2000 ; Vol. 525, No. 2. pp. 483-498.
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AB - 1. Overexpression of cardiac calsequestrin (CSQ) impairs Ca2+ signalling in murine myocytes, leading to marked cardiac hypertrophy. Here we report on contractile, histological and electrophysiological changes accompanying the development of cardiac hypertrophy and failure in CSQ-overexpressing mice. 2. CSQ mice developed contractile dysfunction after 60 days of age, with only 40% survival at 6 months. Four- to 6-month-old CSQ mice revealed biventricular dilatation, cardiomyocyte hypertrophy, patchy interstitial fibrosis and tissue calcifications. 3. Cardiac hypertrophy of CSQ mice was accompanied by progressive P-R and Q-T interval prolongation, conduction blocks, 2-fold prolongation of the ventricular action potential and increased cellular membrane capacitance. 4. Remodelling of ionic currents included marked reduction of both density and absolute magnitude of transient outward (I(to)) and inward rectifying (I(K1)) K+ currents. The density, but not the absolute magnitude, of basal and isoproterenol (isoprenaline)-stimulated Ca2+ current (I(Ca)) was decreased by 42% and the inactivation kinetics of I(Ca) were significantly slowed. Na+ current density was suppressed by 50%, but its steady-state activation and inactivation were shifted to more positive potentials. The density of Na+-Ca2+ exchange current was increased by 35%. 5. In CSQ but not in control myocytes dialysed with cAMP, isoproterenol continued to enhance I(Ca). This apparent lower responsiveness of I(Ca) to cAMP could be reversed by the nonhydrolysable cAMP analogue 8-Br-cAMP or the phosphodiesterase inhibitor IBMX, suggesting high phosphodiesterase activity of CSQ myocytes. 6. In young CSQ mice (< 60 days) with compensated cardiac hypertrophy, only I(to) was significantly suppressed. All other currents remained relatively intact. 7. An increase in cardiac Ca2+-storage capability by overexpression of CSQ results in a dilated cardiomyopathy with tissue fibrosis, calcifications, impaired β-adrenergic signalling and progressive remodelling of ionic currents. The extent of the changes in ionic currents was age dependent.

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