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. 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.

Protein kinases in cardiovascular diseases

“…ROCK was reported to be involved in the developmental process of the atrioventricular node, and the alteration of ROCK expression causes atrioventricular conduction disorders in mice. Embryos treated with ROCK inhibitor Y-27632 exhibited first-, second-, and third-degree atrioventricular block with different degrees of morphological abnormalities, [ 105 ] which provides a theoretical basis for further research on the pathophysiology and treatment of atrioventricular block. In addition, AMPK was also found to regulate human intrinsic heart rate.…”

The State of Cardiovascular Developmental Biology is Strong — Honoring Dr. Roger Markwald and his Seminal Contributions to the Field

“…In the study, RHOA‐ROCK signaling was chemically inhibited in avian embryos, resulting in hypoplasia of the AV node with associated AV conduction delay and, in some cases, first‐, second‐, and third‐degree AV block. From the data collected, the authors conclude that RHOA‐ROCK signaling is essential for normal development of the parts of the conduction system, specifically for the normal formation of the myocardial continuity between the sinus venosus and AV node but possibly also for the compact part of the AV node (Kelder et al, ).…”