Disruption of RHOA‐ROCK Signaling Results in Atrioventricular Block and Disturbed Development of the Putative Atrioventricular Node

ABSTRACT The RHOA‐ROCK signaling pathway is involved in numerous developmental processes, including cell proliferation, differentiation and migration. RHOA is expressed in the atrioventricular node (AVN) and altered expression of RHOA results in atrioventricular (AV) conduction disorders in mice. Th...

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Published in:Anatomical record (Hoboken, N.J. : 2007) N.J. : 2007), 2019-01, Vol.302 (1), p.83-92
Main Authors: Kelder, Tim P., Vicente‐Steijn, Rebecca, Poelmann, Robert E., Schalij, Martin J., Deruiter, Marco C., Jongbloed, Monique R. M., Gittenberger‐de Groot, Adriana C.
Format: Article
Language:English
Subjects:
Animals
Atrioventricular Block - metabolism
Atrioventricular Block - physiopathology
atrioventricular conduction disturbances
atrioventricular node
Atrioventricular Node - drug effects
Atrioventricular Node - growth & development
Atrioventricular Node - metabolism
avian model
Canals (anatomy)
Cell Differentiation
Cell migration
Cell proliferation
Chick Embryo
Chickens
developmental biology
Electrocardiography
Embryos
Enzyme inhibitors
Heart
Hypoplasia
Ion channels (cyclic nucleotide-gated)
Islet-1 protein
Morphology
Phenotypes
Protein Kinase Inhibitors - pharmacology
rho-Associated Kinases - antagonists & inhibitors
rho-Associated Kinases - metabolism
rhoA GTP-Binding Protein - antagonists & inhibitors
rhoA GTP-Binding Protein - metabolism
RhoA protein
RHOA‐ROCK signaling pathway
Signal Transduction
Sinuses
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Summary:ABSTRACT The RHOA‐ROCK signaling pathway is involved in numerous developmental processes, including cell proliferation, differentiation and migration. RHOA is expressed in the atrioventricular node (AVN) and altered expression of RHOA results in atrioventricular (AV) conduction disorders in mice. The current study aims to detect functional AVN disorders after disturbing RHOA‐ROCK signaling in chicken embryos. RHOA‐ROCK signaling was inhibited chemically by using the Rho‐kinase inhibitor compound Y‐27632 in avian embryos (20 experimental and 29 control embryos). Morphological examination of control embryos show a myocardial sinus venosus to atrioventricular canal continuity, contributing to the transitional zone of the AVN. ROCK inhibited embryos revealed lateralization and diminished myocardial sinus venosus to atrioventricular canal continuity and at the severe end of the phenotype hypoplasia of the AVN region. Ex ovo micro‐electrode recordings showed an AV conduction delay in all treated embryos as well as cases with first, second (Wenkebach and Mobitz type) and third‐degree AV block which could be explained by the spectrum of severity of the morphological phenotype. Laser capture microdissection and subsequent qPCR of tissue collected from this region revealed disturbed expression of HCN1, ISL1, and SHOX2. We conclude that RHOA‐ROCK signaling is essential for normal morphological development of the myocardial continuity between the sinus venosus and AVN, contributing to the transitional zone, and possibly the compact AVN region. Disturbing the RHOA‐ROCK signaling pathway results in AV conduction disturbances including AV block. The RHOA‐ROCK inhibition model can be used to further study the pathophysiology and therapeutic strategies for AV block. Anat Rec, 302:83–92, 2019. © 2018 Wiley Periodicals, Inc.
ISSN:1932-8486
1932-8494
DOI:10.1002/ar.23912