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Cardiovascular Research Advance Access first published online on October 30, 2009
This version [Corrected Proof] published online on November 23, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp353
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Connexin43 knockdown or overexpression modulates cell coupling in control and failing rabbit left ventricular myocytes

Xun Ai*, Weiwei Zhao and Steven M. Pogwizd

Division of Cardiovascular Disease, Department of Medicine, UAB Center for Cardiovascular Biology, UAB Center for Aging, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall B140, Birmingham, AL 35294, USA

* Corresponding author. Tel: +1 205 934 1361, Fax: +1 205 934 1268, Email: xai{at}uab.edu

Aims: We have shown that failing human and rabbit left ventricle (LV) exhibits downregulation and dephosphorylation of connexin43 (Cx43) and that Cx43 dephosphorylation in heart failure (HF) contributes to reduced cell coupling. However, the role of Cx43 downregulation per se in impaired coupling in HF is unclear.

Methods and results: First, we used adenovirus (Ad) encoding a Cx43 siRNA sequence to knock down Cx43 protein levels in cultured control rabbit LV myocytes. Cells cultured for up to 48 h with intermittent pacing maintained Cx43 protein levels and phosphorylation status. Cell coupling in Cx43 knockdown myocyte pairs (by Lucifer Yellow dye transfer) was markedly reduced after 24 h infection (associated with ~40% Cx43 knockdown) and after 48 h (associated with ~70% Cx43 knockdown). The phosphorylation status, distribution of remaining Cx43 proteins, and levels of other cardiac connexins (Cx40 and Cx45) were unchanged. Second, we overexpressed Cx43 to levels comparable to control using an adenovirus encoding wild-type Cx43 (Cx43WT) gene in isolated LV myocytes from our arrhythmogenic HF rabbit model. We found 87% more Cx43WT proteins improved dye coupling [vs. Ad-β-galactosidase (LacZ) infected HF controls]. Overexpressed Cx43 protein was located throughout the myocyte membrane (same pattern as in controls), and the phosphorylation status of Cx43 remained comparable to that in AdLacZ infected HF controls.

Conclusion: In addition to Cx43 dephosphorylation, downregulation of Cx43 plays an essential role in reduced cell coupling in the failing rabbit heart. Modulation of Cx43 expression could be a novel therapeutic approach to improve conduction and decrease sudden death in HF.

KEYWORDS Connexin43; Protein expression; Intercellular coupling; Heart failure; Arrhythmia

Time for primary review: 48 days


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