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(Circulation Research. 2006;99:1216.)
© 2006 American Heart Association, Inc.

Cellular Biology

Relative Contributions of Connexins 40 and 43 to Atrial Impulse Propagation in Synthetic Strands of Neonatal and Fetal Murine Cardiomyocytes

Philippe Beauchamp, Kathryn A. Yamada, Alex J. Baertschi, Karen Green, Evelyn M. Kanter, Jeffrey E. Saffitz, André G. Kléber

From the Department of Physiology (P.B., A.G.K.), University of Bern, Switzerland; Department of Neuroscience (A.J.B.), University of Geneva, Switzerland; and the Department of Medicine and Center for Cardiovascular Research (K.A.Y., E.M.K., J.E.S.) and the Department of Pathology (K.G., J.E.S.), Washington University, St Louis, Mo. Present address for J.E.S.: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass.

Correspondence to André G. Kléber, MD, Department of Physiology, University of Bern, Bühlplatz5, CH-3012 Bern, Switzerland. E-mail kleber{at}pyl.unibe.ch

Atrial tissue expresses both connexin 40 (Cx40) and 43 (Cx43) proteins. To assess the relative roles of Cx40 and Cx43 in atrial electrical propagation, we synthesized cultured strands of atrial myocytes derived from mice with genetic deficiency in Cx40 or Cx43 expression and measured propagation velocity (PV) by high-resolution optical mapping of voltage-sensitive dye fluorescence. The amount of Cx40 and/or Cx43 in gap junctions was measured by immunohistochemistry and total or sarcolemmal Cx43 or Cx40 protein by immunoblotting. Progressive genetic reduction in Cx43 expression decreased PV from 34±6 cm/sec in Cx43^+/+ to 30±8 cm/sec in Cx43^+/– and 19±11 cm/sec in Cx43^–/– cultures. Concomitantly, the cell area occupied by Cx40 immunosignal in gap junctions decreased from 2.0±1.6% in Cx43^+/+ to 1.7±0.5% in Cx43^+/– and 1.0±0.2% in Cx43^–/– strands. In contrast, progressive genetic reduction in Cx40 expression increased PV from 30±2 cm/sec in Cx40^+/+ to 40±7 cm/sec in Cx40^+/– and 45±10 cm/sec in Cx40^–/– cultures. Concomitantly, the cell area occupied by Cx43 immunosignal in gap junctions increased from 1.2±0.9% in Cx40^+/+ to 2.8±1.4% in Cx40^+/– and 3.1±0.6% in Cx40^–/– cultures. In accordance with the immunostaining results, immunoblots of the Triton X-100–insoluble fraction revealed an increase of Cx43 in gap junctions in extracts from Cx40-ablated atria, whereas total cellular Cx43 remained unchanged. Our results suggest that the relative abundance of Cx43 and Cx40 is an important determinant of atrial impulse propagation in neonatal hearts, whereby dominance of Cx40 decreases and dominance of Cx43 increases local propagation velocity.

Key Words: atrial myocyte • basic science • cardiac gap junction connexins • cardiovascular genomics • cell culture • conduction velocity • connexin 40 • connexin 43 • mapping • neonatal mouse cardiomyocytes • optical mapping

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