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Influence of gelsolin deficiency on excitation contraction coupling in adult murine cardiomyocytes.

Ion channels involved in cardiac excitation-contraction coupling are linked to the cytoskeleton. Therefore changes in the cytoskeletal actin filaments may influence cardiac membrane currents and electro-mechanical coupling. Depolymerization of actin filaments by gelsolin (gsn) is involved in the organisation of the cytoskeleton by leading to a lower polymerization state. Gsn is activated by Ca(2+) and inhibited by phosphoinositol-bisphosphate (PIP2). Furthermore, gsn has been linked to pathological conditions with reduced contractility like heart failure, amyloidosis and apoptosis. Thus, we hypothesize, that gsn deficiency may change electromechanical properties of freshly isolated ventricular cardiomyocytes. We recorded L-type Ca(2+) current (ICa,L) in whole-cell patch clamp mode in freshly isolated ventricular cardiomyocytes from gsn deficient ((-/-)) and control (gsn(+/+)) mice. Sarcomere shortening was monitored in field-stimulated myocytes from 0.5 Hz to 10 Hz by video microscopy. Shortening-frequency relation, post-rest potentiation and β-adrenergic stimulation were investigated. ICa,L was increased in gsn(-/-) vs. gsn(+/+) myocytes. Sarcomere shortening amplitude and velocity were enhanced in gsn(-/-) vs. gsn(+/+) at all frequencies. Shortening-frequency relationship showed a biphasic pattern with decay in shortening amplitude between 0.5 and 2 Hz and an increase at higher frequencies in both genotypes. Post-rest characteristics revealed a frequency-dependent decay of post-rest potentiation in gsn(+/+) while it remained stable in gsn(-/-). In gsn(-/-) a reduced response to β-adrenergic stimulation was observed. Resting sarcomere length was shorter in gsn(-/-) but neither increasing frequency nor β-adrenergic stimulation induced further decay in any of the genotypes. In summary, gsn deficiency had a profound effect on excitiation-contraction properties and improved systolic function while not affecting diastolic function in unloaded isolated cardiomyocytes. Therefore, gsn mediated effects on contractility may play a role in patients with heart failure and cancer, where gsn levels are known to be elevated.