Chronic exposure to interleukin 1beta induces a delayed and reversible alteration in excitation-contraction coupling of cultured cardiomyocytes.
While proinflammatory cytokines can depress cardiac contractility, the mechanism by which this occurs remains unclear. To clarify the cellular effects of interleukin (IL)-1beta, we assessed contractility, calcium homeostasis, and gene expression in cardiomyocytes exposed to this proinflammatory cytokine. Neonatal rat cardiomyocytes were exposed to IL-1beta in the presence or absence of an inhibitor of nitric oxide (NO) synthase. Videomicroscopy was used to follow calcium transients (Fura-2 fluorescence) and amplitude of contraction, both unstimulated and after isoproterenol challenge. Gene expression was assessed by Northern and Western blot analyses. Both basal contractility (amplitude of contraction, maximum speed of contraction and relaxation) and amplitude of calcium transients were decreased, respectively, ca. 60% ( P< or =0.05) and ca. 40% ( P< or =0.05) after 3 days of IL-1beta exposure. Contractile function and amplitude of calcium transients returned to control values when cells where cultured an additional 3 days in the absence of IL-1beta. IL-1beta-treated cells had reduced responses to isoproterenol as evidenced by a lack of enhanced amplitude of contraction and a reduction in cAMP production. IL-1beta decreased the expression of genes important to the regulation of calcium homeostasis (phospholamban, sarcoplasmic reticulum calcium ATPase) at both the transcript and protein level. Alterations in contractile function did not occur through NO-mediated pathways. These results support the hypothesis that IL-1beta may play an important role in contractile dysfunction through alterations in calcium homeostasis.
Combes
Alain
A
Service de Réanimation Médicale, Pr Gibert, Institut de Cardiologie, Hopital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 47 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France. alain.combes@psl.ap-hop-paris.fr
Frye
Carole S
CS
Lemster
Bonnie H
BH
Brooks
Steven S
SS
Watkins
Simon C
SC
Feldman
Arthur M
AM
McTiernan
Charles F
CF
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004334:Drug Administration Schedule; D015870:Gene Expression / Q000187:drug effects; D007375:Interleukin-1 / Q000008:administration & dosage*; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000318:Adrenergic beta-Agonists; D007375:Interleukin-1; D007545:Isoproterenol; D002118:Calcium