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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 R. Jones‡ and Martin Morad

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 non-hydrolysable 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 -adrenergic signalling and progressive remodelling of ionic currents. The extent of the changes in ionic currents was age dependent.

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