Cardiotrophin-1 induces sarcoplasmic reticulum Ca(2+) leak and arrhythmogenesis in adult rat ventricular myocytes.
OBJECTIVE
Plasma levels of cardiotrophin-1 (CT-1) are elevated in several cardiovascular diseases and are correlated with the severity of the pathology. However, the mechanisms by which this inflammatory cytokine participates in the pathology of the heart are not completely understood. It is well established that alterations in intracellular calcium ([Ca(2+)](i)) handling are involved in cardiac dysfunction during heart failure, but it is unknown whether CT-1 modulates [Ca(2+)](i) handling in adult cardiomyocytes. Here we have analyzed for the first time the effects of CT-1 on [Ca(2+)](i) homeostasis in adult rat cardiomyocytes.


RESULTS
L-type calcium current (I(CaL)) was recorded using patch-clamp techniques, and [Ca(2+)](i) transients and Ca(2+) sparks were viewed by confocal microscopy. Treatment of cardiomyocytes with 1 nM CT-1 for 20-60 min induced a significant increase in I(CaL) density, [Ca(2+)](i) transients, and cell shortening compared with control cells. Our study reveals that CT-1 increases I(CaL) by a protein kinase A-dependent mechanism, and Ca(2+) sparks by a Ca(2+)/calmodulin kinase II-dependent and protein kinase A-independent mechanism. Cardiomyocytes treated with CT-1 exhibited a higher occurrence of arrhythmogenic behaviour, manifested as spontaneous Ca(2+) waves and aftercontractions.


CONCLUSIONS
Our findings provide evidence that cardiomyocytes treated with CT-1 present high spontaneous Ca(2+) release during diastole, a mechanism linked to arrhythmogenicity in the pathologic heart.
Inserm, U769, IFR141, Labex Lermit, Université Paris 11, Chatenay-Malabry,  France.
Gema
G
Ruiz-Hurtado
Nieves
N
Gómez-Hurtado
María
M
Fernández-Velasco
Eva
E
Calderón
Tarik
T
Smani
Antonio
A
Ordoñez
Victoria
V
Cachofeiro
Lisardo
L
Boscá
Javier
J
Díez
Ana María
AM
Gómez
Carmen
C
Delgado
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D003971:Diastole; D008297:Male; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
D016207:Cytokines; C092073:cardiotrophin 1; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium