Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 525, Issue 2, Pages 483-498Publisher
WILEY
DOI: 10.1111/j.1469-7793.2000.t01-1-00483.x
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Funding
- NHLBI NIH HHS [R01-HL-16152, R01 HL016152, R01 HL028556, R01-HL-28556] Funding Source: Medline
- NIGMS NIH HHS [GM08386, T32 GM008386] Funding Source: Medline
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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 beta-adrenergic signalling and progressive remodelling of ionic currents. The extent of the changes in ionic currents was age dependent.
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