Remodeling of Gap Junctions in Mouse Hearts Hypertrophied by Forced Retinoic Acid Signaling

T. A. B. van Veen, H. V. M. van Rijen, R. F. Wiegerinck, T. Opthof, M. C. Colbert, S. Clement, J. M. T. de Bakker and H. J. Jongsma. Remodeling of Gap Junctions in Mouse Hearts Hypertrophied by Forced Retinoic Acid Signaling.Journal of Molecular and Cellular Cardiology (2002) 34, 1411–1423. Background: β-MHC-hRARα transgenic mice express a constitutively active (truncated) form of the human retinoic acid receptor which triggers development of dilated cardiomyopathy. In those hearts, we studied expression of gap junction proteins in relation to electrical impulse propagation. Methods and Results: As compared to wildtype mice, hearts of 4–6 month old mice with 7–12 inserted hRARα copies are marked by an increased heart weight/body weight- and heart weight/tibia length ratio. 3-extremity lead ECGs revealed prolongation of the Q–j interval suggesting delayed ventricular activation. Mapping of electrical activity of epi- and endocardial left ventricular free wall revealed activation delay, increased heterogeneity in conduction and regional conduction block. Ventricular tachycardiaʹs did not occur spontaneously nor could be induced by ventricular pacing. Immunohistochemical analysis showed profound and heterogeneous redistribution and down-regulation of the gap junction protein connexin43 (Cx43) in the left ventricular free wall. Here, hRARα expression induced re-expression of the hypertrophic markers α-skeletal actin and β-MHC, and in 3 out of 10 severely affected mice, re-expression of Cx40. Concomitant with changes in expression/distribution of Cx43, changes in expression and distribution of β-catenin and N-cadherin (two other intercalated disk associated proteins) were observed. Conclusions: β-MHC-hRARα transgenic hearts show heterogeneous re-expression of (early) sarcomeric genes while expression of connexin43, N-cadherin and β-catenin is down-regulated. We postulate that the resulting aberrant ventricular activation does not trigger development of lethal arrhythmias due to the small size of remaining healthy ventricular tissue where the transgene is not expressed.