Wnt-1 regulation of connexin43 in cardiac myocytes

Zhaowei Ai, Avi Fischer, David C. Spray, Anthony M C Brown, Glenn I. Fishman

Research output: Contribution to journalArticle

290 Citations (Scopus)

Abstract

Gap junction channels composed of connexin43 (Cx43) are essential for normal heart formation and function. We studied the potential role of the Wnt family of secreted polypeptides as regulators of Cx43 expression and gap junction channel function in dissociated myocytes and intact hearts. Neonatal rat cardiomyocytes responded to Li+, which mimics Wnt signaling, by accumulating the effector protein β-catenin and by inducing Cx43 mRNA and protein markedly. Induction of Cx43 expression was also observed in cardiomyocytes cocultured with Rat-2 fibroblasts or N2A neuroblastoma cells programmed to secrete bioactive Wnt-1. By transfecting a Cx43 promoter- reporter gene construct into cardiomyocytes, we demonstrated that the inductive effect of Wnt signaling was transcriptionally mediated. Enhanced expression of Cx43 increased cardiomyocyte cell coupling, as determined by Lucifer Yellow dye transfer and by calcium wave propagation. Conversely, in a transgenic cardiomyopathic mouse model that exhibits ventricular arrhythmias and gap junctional remodeling, β-catenin and Cx43 expression were downregulated concordantly. In response to Wnt signaling, the accumulating Cx43 colocalized with β-catenin in the junctional membrane; moreover, forced expression of Cx43 in cardiomyocytes reduced the transactivation potential of β-catenin. These findings demonstrate that Wnt signaling is an important modulator of Cx43-dependent intercellular coupling in the heart, and they support the hypothesis that dysregulated signaling contributes to altered impulse propagation and arrhythmia in the myopathic heart.

Original languageEnglish (US)
Pages (from-to)161-171
Number of pages11
JournalJournal of Clinical Investigation
Volume105
Issue number2
StatePublished - Jan 2000

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Connexin 43
Cardiac Myocytes
Catenins
Gap Junctions
Cardiac Arrhythmias
Calcium Signaling
Neuroblastoma
Reporter Genes
Muscle Cells
Transgenic Mice
Transcriptional Activation
Coloring Agents
Down-Regulation
Fibroblasts
Messenger RNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ai, Z., Fischer, A., Spray, D. C., Brown, A. M. C., & Fishman, G. I. (2000). Wnt-1 regulation of connexin43 in cardiac myocytes. Journal of Clinical Investigation, 105(2), 161-171.

Wnt-1 regulation of connexin43 in cardiac myocytes. / Ai, Zhaowei; Fischer, Avi; Spray, David C.; Brown, Anthony M C; Fishman, Glenn I.

In: Journal of Clinical Investigation, Vol. 105, No. 2, 01.2000, p. 161-171.

Research output: Contribution to journalArticle

Ai, Z, Fischer, A, Spray, DC, Brown, AMC & Fishman, GI 2000, 'Wnt-1 regulation of connexin43 in cardiac myocytes', Journal of Clinical Investigation, vol. 105, no. 2, pp. 161-171.
Ai Z, Fischer A, Spray DC, Brown AMC, Fishman GI. Wnt-1 regulation of connexin43 in cardiac myocytes. Journal of Clinical Investigation. 2000 Jan;105(2):161-171.
Ai, Zhaowei ; Fischer, Avi ; Spray, David C. ; Brown, Anthony M C ; Fishman, Glenn I. / Wnt-1 regulation of connexin43 in cardiac myocytes. In: Journal of Clinical Investigation. 2000 ; Vol. 105, No. 2. pp. 161-171.
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