Remodeling of gap junctions in mouse hearts hypertrophied by forced retinoic acid signaling.
BACKGROUND
Beta-MHC-hRARalpha 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.


RESULTS
As compared to wildtype mice, hearts of 4-6 month old mice with 7-12 inserted hRARalpha 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 tachycardias 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, hRARalpha expression induced re-expression of the hypertrophic markers alpha-skeletal actin and beta-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 beta-catenin and N-cadherin (two other intercalated disk associated proteins) were observed.


CONCLUSIONS
Beta-MHC-hRARalpha transgenic hearts show heterogeneous re-expression of (early) sarcomeric genes while expression of connexin43, N-cadherin and beta-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.
van Veen
Toon A B
TA
Department of Medical Physiology, University Medical Center Utrecht, PO Box 85060, 3508 AB Utrecht, The Netherlands. A.A.B.vanVeen@med.uu.nl
van Rijen
Harold V M
HV
Wiegerinck
Rob F
RF
Opthof
Tobias
T
Colbert
Melissa C
MC
Clement
Sophie
S
de Bakker
Jacques M T
JM
Jongsma
Habo J
HJ
D000199:Actins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D001835:Body Weight; D015820:Cadherins / Q000378:metabolism; D006332:Cardiomegaly / Q000473:pathology*; D018031:Connexin 43 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015536:Down-Regulation; D004558:Electric Stimulation; D004562:Electrocardiography; D017629:Gap Junctions / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology*; D009929:Organ Size; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*; D051176:beta Catenin
D000199:Actins; D015415:Biomarkers; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D018031:Connexin 43; D003598:Cytoskeletal Proteins; D018168:Receptors, Retinoic Acid; D015534:Trans-Activators; D051176:beta Catenin; D014212:Tretinoin