127 Developmental rock downregulation disrupts sarcomeric structure resulting in the development of hypertrophic cardiomyopathy. (May 2019)

• Record Type: Journal Article
• Authors: Bailey, Kate; MacGowan, Guy; Tual-Chalot, Simon; Phillips, Lauren; Mohun, Timothy J; Henderson, Deborah J; Arthur, Helen; Bamforth, Simon; Phillips, Helen M
• Is Part Of: Heart. Volume 105(2019)Supplement 6
• Page Start: A104
• Page End: A104
• Publication Date: 2019-05
• Subjects: Rho Kinase -- Sarcomeres -- Hypertrophic cardiomyopathy; Heart -- Diseases -- Treatment -- Periodicals; Cardiology -- Periodicals; 616.12
• DOI: 10.1136/heartjnl-2019-BCS.124
• Languages: English
• ISSNs: 1355-6037

Abstract

Abstract : Introduction: Congenital heart defects are common, affecting ∼1% of live births, while adult heart disease is the main cause of death in the UK. Defects acquired during foetal development can have a lasting detrimental effect on adult heart function. Therefore, understanding the underlying mechanisms involved in cardiac development and disease progression are of particular importance. Cardiomyopathy is a disease of the heart muscle. Hypertrophic cardiomyopathy (HCM) is one of the most common forms of cardiomyopathy; mutations have been identified in the troponin complex, a key component of the sarcomere, signifying that disruption to sarcomeric integrity plays an important role in disease progression. Rho Kinase (ROCK) is expressed in the heart during development and is known to be a regulator of actin-myosin contraction through the phosphorylation of the troponin complex. Our aim was to determine the effect of developmental ROCK downregulation on sarcomeric integrity and impact this had on the function of the adult heart. Methods: Cre-LoxP technology was utilised to create a conditional mouse model in which ROCK was specifically downregulated in the cardiomyocytes from E9.25, during cardiac development. Histological techniques were used to assess the embryonic and adult heart phenotype. Analysis of the cytoarchitecture was performed by TEM while cine cardiac MRI was used to assess overall adult heart function. Results: and Conclusions: Developmental downregulation of ROCK in the cardiomyocytes resulted in loss of sarcomere integrity at E10.5, associated with a reduction in the levels of phosphorylation of cardiac Troponin I and T, and reduced cardiomyocyte proliferation at E11.5. This caused abnormal myocardial wall development, where the compact myocardium failed to thicken. The impact of these embryonic abnormalities, triggered compensatory foetal cardiomyocyte hypertrophy, which persisted throughout postnatal development and into adult life. Over time this continued hypertrophy became detrimental, triggering cardiac remodelling. Mutants exhibit key features of HCM including concentric hypertrophy with systolic dysfunction, fibrosis and re-expression of foetal genes. This data suggests a novel developmental origin of the sarcomeric phenotype of HCM and indicates disruption in ROCK signalling may contribute to the pathogenesis of HCM. (Bailey et al., Disruption of embryonic ROCK signalling reproduces the sarcomeric phenotype of Hypertrophic Cardiomyopathy. JCI Insight, in press) Conflict of Interest: None