December 1, 2000AJP Heart and Circulatory Physiology
Cellular and functional defects in a mouse model of heart failure
Why the study?
Does a cardiac-targeted transgene blocking betaARK1 improve cellular and whole heart function in MLP(-/-) mice with heart failure?
Population
Mice lacking the muscle LIM protein gene (MLP) that develop heart failure and dilated cardiomyopathy
Design
Preclinical
Authors
Discussion
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Implication
Should not yet alter clinical practice; extends preclinical evidence for betaARK1 inhibition in heart failure.
Key Points
- Investigate the cellular and hemodynamic mechanisms underlying dilated cardiomyopathy and heart failure in muscle LIM protein-deficient mice, and evaluate potential rescue through betaARK1 inhibition.
- Assessed in vivo hemodynamics and ventricular pressure-volume loops in MLP(-/-) mice using echocardiography and sonomicrometry with implanted orthogonal piezoelectric crystals.
- Measured single-cell calcium currents, calcium spark characteristics, and excitation-contraction coupling using patch-clamp electrophysiology and confocal calcium imaging.
- Expressed a cardiac-targeted transgene that inhibits beta-adrenergic receptor kinase-1 (betaARK1) to evaluate potential functional rescue.
- MLP(-/-) mice demonstrated right-shifted pressure-volume loops, markedly depressed systolic contractility, and overt signs of heart failure in vivo.
- Isolated cardiomyocytes exhibited preserved calcium currents and spark properties, but displayed decreased intracellular calcium transients, blunted contractility, and disrupted excitation-contraction coupling.
- Targeted transgenic inhibition of betaARK1 restored both single-cell excitation-contraction coupling and whole-heart systolic performance to normal levels.
Structured PICO
Does a cardiac-targeted transgene blocking betaARK1 improve cellular and whole heart function in MLP(-/-) mice with heart failure?
P
Population
Mice lacking the muscle LIM protein (MLP) gene (MLP(-/-)) that develop heart failure and dilated cardiomyopathy
I
Intervention
Cardiac-targeted transgene that blocks the function of beta-adrenergic receptor (beta-AR) kinase-1 (betaARK1)
O
Outcome
Cellular and whole heart function assessed via echocardiography, in vivo pressure-volume (P-V) loop measurements, patch-clamp, and confocal Ca(2+) concentration imagingsurrogate
Inhibition of betaARK1 restores normal cellular and whole heart function in a mouse model of heart failure, suggesting it may be an effective therapeutic target.
Cite This Study
Esposito et al. (2000) studied this question.