RESUMO
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.
Assuntos
Cardiomiopatia Hipertrófica/genética , Ventrículos do Coração/patologia , Sarcômeros/patologia , Quinases Associadas a rho/genética , Animais , Cardiomiopatia Hipertrófica/patologia , Modelos Animais de Doenças , Embrião de Mamíferos , Ventrículos do Coração/citologia , Ventrículos do Coração/embriologia , Humanos , Mutação com Perda de Função , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/patologia , Sarcômeros/metabolismo , Quinases Associadas a rho/metabolismoRESUMO
We report draft genome sequences of 40 Pseudomonas aeruginosa strains, isolated from the sputum of a single cystic fibrosis patient over eight years. Analyses indicated a correlation between multidrug-resistant phenotypes and population structure. Our data provide new insights into the mechanisms leading to acquisition of antibiotic resistance in P. aeruginosa.