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1.
JCI Insight ; 4(19)2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31513548

RESUMO

Perturbations in biomechanical stimuli during cardiac development contribute to congenital cardiac defects such as hypoplastic left heart syndrome (HLHS). This study sought to identify stretch-responsive pathways involved in cardiac development. miRNA-Seq identified miR-486 as being increased in cardiomyocytes exposed to cyclic stretch in vitro. The right ventricles (RVs) of patients with HLHS experienced increased stretch and had a trend toward higher miR-486 levels. Sheep RVs dilated from excessive pulmonary blood flow had 60% more miR-486 compared with control RVs. The left ventricles of newborn mice treated with miR-486 mimic were 16.9%-24.6% larger and displayed a 2.48-fold increase in cardiomyocyte proliferation. miR-486 treatment decreased FoxO1 and Smad signaling while increasing the protein levels of Stat1. Stat1 associated with Gata-4 and serum response factor (Srf), 2 key cardiac transcription factors with protein levels that increase in response to miR-486. This is the first report to our knowledge of a stretch-responsive miRNA that increases the growth of the ventricle in vivo.


Assuntos
Ventrículos do Coração/crescimento & desenvolvimento , Síndrome do Coração Esquerdo Hipoplásico/genética , MicroRNAs/metabolismo , Animais , Animais Recém-Nascidos , Fenômenos Biomecânicos , Proliferação de Células/fisiologia , Células Cultivadas , Ventrículos do Coração/metabolismo , Humanos , Síndrome do Coração Esquerdo Hipoplásico/patologia , Síndrome do Coração Esquerdo Hipoplásico/fisiopatologia , Mecanotransdução Celular/fisiologia , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Fator de Transcrição STAT1/metabolismo , Ovinos
2.
J Mol Cell Cardiol ; 79: 133-44, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25446186

RESUMO

Perturbed biomechanical stimuli are thought to be critical for the pathogenesis of a number of congenital heart defects, including Hypoplastic Left Heart Syndrome (HLHS). While embryonic cardiomyocytes experience biomechanical stretch every heart beat, their molecular responses to biomechanical stimuli during heart development are poorly understood. We hypothesized that biomechanical stimuli activate specific signaling pathways that impact proliferation, gene expression and myocyte contraction. The objective of this study was to expose embryonic mouse cardiomyocytes (EMCM) to cyclic stretch and examine key molecular and phenotypic responses. Analysis of RNA-Sequencing data demonstrated that gene ontology groups associated with myofibril and cardiac development were significantly modulated. Stretch increased EMCM proliferation, size, cardiac gene expression, and myofibril protein levels. Stretch also repressed several components belonging to the Transforming Growth Factor-ß (Tgf-ß) signaling pathway. EMCMs undergoing cyclic stretch had decreased Tgf-ß expression, protein levels, and signaling. Furthermore, treatment of EMCMs with a Tgf-ß inhibitor resulted in increased EMCM size. Functionally, Tgf-ß signaling repressed EMCM proliferation and contractile function, as assayed via dynamic monolayer force microscopy (DMFM). Taken together, these data support the hypothesis that biomechanical stimuli play a vital role in normal cardiac development and for cardiac pathology, including HLHS.


Assuntos
Embrião de Mamíferos/citologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Estresse Mecânico , Fator de Crescimento Transformador beta/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Tamanho Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Camundongos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miofibrilas/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia
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