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Disruption of embryonic ROCK signalling reproduces the sarcomeric phenotype of Hypertrophic Cardiomyopathy

Lookup NU author(s): Dr Kate Bailey, Dr Guy MacGowanORCiD, Dr Simon Tual-Chalot, Lauren Charlotte Phillips Phillips, Professor Deborah HendersonORCiD, Professor Helen ArthurORCiD, Dr Helen PhillipsORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Sarcomeric disarray is a hallmark of gene mutations in patients with Hypertrophic Cardiomyopathy (HCM). However, it is unknown when detrimental sarcomeric changes first occur and whether they originate in the developing embryonic heart. Furthermore, Rho Kinase (ROCK) is a serine threonine protein kinase that is critical for regulating the function of several sarcomeric proteins and therefore, our aim was to determine if disruption of ROCK signalling during the earliest stages of heart development would disrupt the integrity of sarcomeres altering heart development and function. Using a mouse model in which the function of ROCK is specifically disrupted in embryonic cardiomyocytes we demonstrate a progressive cardiomyopathy that first appeared as sarcomeric disarray during cardiogenesis. This led to abnormalities in the structure of embryonic ventricular wall and compensatory cardiomyocyte hypertrophy during foetal development. This sarcomeric disruption and hypertrophy persisted throughout adult life, triggering left ventricular concentric hypertrophy with systolic dysfunction, and re-activation of foetal gene expression and cardiac fibrosis, all typical features of HCM. Taken together, our findings establish a novel mechanism for the developmental origin of the sarcomeric phenotype of HCM and suggest that variants in the ROCK genes or disruption of ROCK signalling could, in part, contribute to its pathogenesis.

Publication metadata

Author(s): Bailey KE, MacGowan GA, Tual-Chalot S, Phillips L, Mohun TJ, Henderson DJ, Arthur HM, Bamforth SD, Phillips HM

Publication type: Article

Publication status: Published

Journal: JCI Insight

Year: 2019

Volume: 4

Issue: 8

Print publication date: 18/04/2019

Online publication date: 05/03/2019

Acceptance date: 28/02/2019

Date deposited: 04/03/2019

ISSN (electronic): 2379-3708

Publisher: American Society for Clinical Investigation


DOI: 10.1172/jci.insight.125172


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Funder referenceFunder name
British Heart Foundation