Cardiotrophin-1: Another “player” in Cardiac Calcium Handling

Abstract

Cardiotrophin-1 (CT-1) is a cytokine member of the interleukin-6 superfamily produced by cardiomyocytes and fibroblasts in the heart, in situations of haemodynamic overload, or in the presence of humoral factors as aldosterone. CT-1 is able to induce hypertrophic growth and dysfunction of cardiomyocytes in vitro. Moreover, plasma levels of CT-1 are elevated in patients with cardiac hypertrophy and heart failure (HF) and correlated with the severity of the disease. On the other hand, it is well established that alterations in calcium handling are involved in cardiac dysfunction during HF. However, it is yet unknown whether CT-1 modulates Ca2+handling in cardiomyocytes. Here we analyzed CT-1 effects on [Ca2+]i handling in rat single cardiomyocytes. The L-type calcium current (ICaL) was registered using whole-cell patch-clamp technique. Intracellular calcium [Ca2+]i transients and Ca2+ sparks were viewed by confocal miscroscopy in cardiomyocytes loaded with the fluorescence Ca2+ indicator Fluo-3 AM. Treatment of cardiomyocytes with 1 nM CT-1 for 30 min induced a significant increase in ICaL density compared to control cells (at −10 mV: −16.0 ± 0.9 vs. 11.9± 0.7 pA/pF; P< 0.01). The activity of ryanodine receptors (RyRs), estimated by Ca2+ spark frequency, was significantly increased in cardiomyocytes treated with CT-1 (Ca2+ sparks·s−1·100 μm−1: 2.3 ± 0.3 vs. 4.3 ± 0.5; P< 0.01). Moreover, we observed that the increase in the total Ca2+ spark frequency produced by CT-1 could be attributable to the increased propensity of some clusters of RyR to release Ca2+repetitively. Thus, we conclude that CT-1 is able to alter Ca2+ handling in isolated cardiomyocytes, enhancing the Ca2+ influx through L-type Ca2+ channel and the Ca2+release from sarcoplasmic reticulum through RyRs.