125172.2-20190328154301-covered-253bed37ca4c1ab43d105aefdf7b5536.pdf (4.68 MB)

Disruption of embryonic ROCK signalling reproduces the sarcomeric phenotype of hypertrophic cardiomyopathy

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posted on 11.12.2019 by Kate E Bailey, Guy A MacGowan, Simon Tual-Chalot, Lauren Phillips, Tim J Mohun, Deborah J Henderson, Helen M Arthur, Simon D Bamforth, Helen M Phillips
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.

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