CCN2 exerts direct cytoprotective actions in adult cardiac myocytes by activation of the PI3-kinase-Akt-GSK-3β signaling pathwayReportar como inadecuado

CCN2 exerts direct cytoprotective actions in adult cardiac myocytes by activation of the PI3-kinase-Akt-GSK-3β signaling pathway - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal of Cell Communication and Signaling

, Volume 7, Issue 1, pp 31–47

First Online: 04 December 2012Received: 31 October 2012Accepted: 05 November 2012DOI: 10.1007-s12079-012-0183-1

Cite this article as: Moe, I.T., Pham, T.A., Hagelin, E.M.V. et al. J. Cell Commun. Signal. 2013 7: 31. doi:10.1007-s12079-012-0183-1


We recently reported that transgenic mice with cardiac-restricted overexpression of CCN2-CTGF have substantially increased tolerance towards ischemia-reperfusion injury. The purpose of this study was to investigate to what extent fully differentiated cardiac myocytes are direct targets of CCN2, and to resolve the signaling mechanisms that convey the cardioprotective actions of CCN2. Akt and GSK-3β were identified as putative intermediaries of intracellular signaling stimulated by recombinant human CCN2 rhCCN2. Concentration-effect experiments revealed CCN2-stimulated phosphorylation of Akt Ser473 and downstream GSK-3β Ser9 with EC50 ~250 nmol-L. CCN2-stimulated phosphorylation of Akt and GSK-3β was sensitive to inhibition of PI3-kinase LY294002. Phosphorylation of GSK-3β was also sensitive to Akt-inhibition API-2, demonstrating CCN2-engendered activation of a PI3-kinase-Akt-GSK-3β-signaling pathway. A C-terminal peptide fragment of CCN2 11.2 kD displayed partial agonist activity, while two short peptides derived from the Thrombospondin- and the IGFBP- homology domains of CCN2, respectively, additively inhibited rhCCN2-stimulated Akt-phosphorylation. The viability of cardiac myocytes subjected to hypoxia-reoxygenation injury or doxorubicin-induced oxidative stress was assessed by assays of adenylate kinase and lactate dehydrogenase released from dying cells. Cardiac myocytes exposed to CCN2 displayed increased tolerance towards hypoxia-reoxygenation and doxorubicin-induced oxidative stress, an effect that was abrogated by inhibition of PI3-kinase. The cytoprotective actions of CCN2 reflected in the transcriptome of CCN2-stimulated cardiac myocytes anti-apoptosis, stress, and wound-response gene programs. In conclusion, this study discloses the novel findings that cardiac myocytes are CCN2 target cells in which CCN2 increases tolerance towards hypoxia and oxidative stress via PI3-kinase-dependent Akt-GSK-3β signaling.

KeywordsCCN2-CTGF Cardiac myocyte Cytoprotection Cardioprotection Signaling Akt-GSK-3β AbbreviationsrhCCN2Recombinant full-length, human CCN2

GSK-3βGlycogen synthase kinase 3 beta

AKAdenylate kinase

LDHLactate dehydrogenase

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Autor: Ingvild Tronstad Moe - Tuyet Anh Pham - Else Marie Valbjørn Hagelin - Mohammad Shakil Ahmed - Håvard Attramadal


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