title: Absence of suppressor of cytokine signaling 2 turns cardiomyocytes unresponsive to LIF-dependent increases in Ca2+levels.
abstract: Little is known regarding the role of suppressor of cytokine signaling (SOCS) in the control of cytokine signaling in cardiomyocytes. We investigated the consequences of SOCS2 ablation for leukemia inhibitory factor (LIF)-induced enhancement of intracellular Ca2+([Ca2+]i) transient by performing experiments with cardiomyocytes from SOCS2-knockout (ko) mice. Similar levels of SOCS3 transcripts were seen in cardiomyocytes from wild-type and SOCS2-ko mice, while SOCS1 mRNA was reduced in SOCS2-ko. Immunoprecipitation experiments showed increased SOCS3 association with gp130 receptor in SOCS2-ko myocytes. Measurements of Ca2+in wild-type myocytes exposed to LIF showed a significant increase in the magnitude of the Ca2+transient. This change was absent in LIF-treated SOCS2-ko cells. LIF activation of ERK and STAT3 was observed in both wild-type and SOCS2-ko cells, indicating that in SOCS2-ko, LIF receptors were functional, despite the lack of effect in the Ca2+transient. In wild-type cells, LIF-induced increase in [Ca2+]iand phospholamban Thr17 [PLN(Thr17)] phosphorylation was inhibited by KN-93, indicating a role for CaMKII in LIF-induced Ca2+raise. LIF-induced phosphorylation of PLN(Thr17) was abrogated in SOCS2-ko myocytes. In wild-type cardiomyocytes, LIF treatment increased L-type Ca2+current (ICa,L), a key activator of CaMKII in response to LIF. Conversely, SOCS2-ko myocytes failed to activateICa,Lin response to LIF, providing a rationale for the lack of LIF effect on Ca2+transient. Our data show that absence of SOCS2 turns cardiomyocytes unresponsive to LIF-induced [Ca2+] raise, indicating that endogenous levels of SOCS2 are crucial for full activation of LIF signaling in the heart.
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Cibele
authors.initials: C
authors.lastname: Rocha-Resende
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Itamar Couto
authors.initials: IC
authors.lastname: Guedes de Jesus
authors.affiliation: Department of Biophysics, Paulista School of Medicine, Universidade Federal de São Paulo, Sao Paulo, Brazil.
authors.forename: Danilo
authors.initials: D
authors.lastname: Roman-Campos
authors.affiliation: Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; and.
authors.forename: Artur S
authors.initials: AS
authors.lastname: Miranda
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Alves
authors.affiliation: Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; and.
authors.forename: Rodrigo Ribeiro
authors.initials: RR
authors.lastname: Resende
authors.affiliation: Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; and.
authors.forename: Jader
authors.initials: J
authors.lastname: Dos Santos Cruz
authors.affiliation: Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; and.
authors.forename: Fabiana Simão
authors.initials: FS
authors.lastname: Machado
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; guatimosim@icb.ufmg.br.
authors.forename: Silvia
authors.initials: S
authors.lastname: Guatimosim
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology; D053605:Leukemia Inhibitory Factor / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000502:physiology*; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; C491409:Socs2 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D002118:Calcium
keywords: SOCS; calcium; leukemia inhibitory factor; signaling pathways; ventricular myocyte