RESUMO
Understanding the regulation of cardiac fibrosis is critical for controlling adverse cardiac remodeling during heart failure. Previously we identified miR-378 as a cardiomyocyte-abundant miRNA down-regulated in several experimental models of cardiac hypertrophy and in patients with heart failure. To understand the consequence of miR-378 down-regulation during cardiac remodeling, our current study employed a locked nucleic acid-modified antimiR to target miR-378 in vivo. Results showed development of cardiomyocyte hypertrophy and fibrosis in mouse hearts. Mechanistically, miR-378 depletion was found to induce TGFß1 expression in mouse hearts and in cultured cardiomyocytes. Among various secreted cytokines in the conditioned-media of miR-378-depleted cardiomyocytes, only TGFß1 levels were found to be increased. The increase was prevented by miR-378 expression. Treatment of cardiac fibroblasts with the conditioned media of miR-378-depleted myocytes activated pSMAD2/3 and induced fibrotic gene expression. This effect was counteracted by including a TGFß1-neutralizing antibody in the conditioned-medium. In cardiomyocytes, adenoviruses expressing dominant negative N-Ras or c-Jun prevented antimiR-mediated induction of TGFß1 mRNA, documenting the importance of Ras and AP-1 signaling in this response. Our study demonstrates that reduction of miR-378 during pathological conditions contributes to cardiac remodeling by promoting paracrine release of profibrotic cytokine, TGFß1 from cardiomyocytes. Our data imply that the presence in cardiomyocyte of miR-378 plays a critical role in the protection of neighboring fibroblasts from activation by pro-fibrotic stimuli.
Assuntos
Fibrose Endomiocárdica/metabolismo , MicroRNAs/biossíntese , Miócitos Cardíacos/metabolismo , Comunicação Parácrina , Fator de Crescimento Transformador beta1/metabolismo , Animais , Caenorhabditis elegans , Células Cultivadas , Fibrose Endomiocárdica/genética , Fibrose Endomiocárdica/patologia , Regulação da Expressão Gênica/genética , Camundongos , MicroRNAs/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/genética , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Fator de Crescimento Transformador beta1/genéticaRESUMO
An increasing body of research indicates that annular stability plays a key role for a successful aortic valve repair. The aim of this study was to evaluate and compare a novel open aortic annuloplasty ring (the A-ring) with the Dacron ring. Both rings were compared with native aortic roots in vitro. Eighteen aortic roots were included in the study and randomized into three groups: the native, Dacron, and A-ring group. The roots were evaluated in an in vitro physiologic pulsatile model simulating the left side of the heart. Aortic annulus diameters were significantly reduced both in the Dacron ring group (p = 0.003) and the A-ring group (p = 0.020) when compared with the native group. Both the Dacron ring and A-ring effectively downsized the aortic annulus diameter. The A-ring also displayed an ability to maintain aortic root distensibility during the cardiac cycle equally to the Dacron ring.
Assuntos
Insuficiência da Valva Aórtica , Anuloplastia da Valva Cardíaca , Próteses Valvulares Cardíacas , Humanos , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Polietilenotereftalatos , Desenho de Prótese , Anuloplastia da Valva Cardíaca/efeitos adversosRESUMO
Continuous video-electroencephalography (EEG) is an important diagnostic and prognostic tool in newborns with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia. The optimal duration of continuous video-EEG during whole-body hypothermia is not known. We conducted a retrospective study of 35 neonates with hypoxic-ischemic encephalopathy undergoing whole-body hypothermia with continuous video-EEG. EEG ictal changes were detected in 9/35 infants (26%). Of these 9 infants, the seizures were initially observed within 30 minutes of EEG monitoring in 6 (67%), within 24 hours in 2 (22%), and during rewarming in 1 infant (11%). No new seizures were detected between 24-72 hours of therapeutic hypothermia. Background suppression was detected in 14 infants (40%) by 24 hours. In neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia, continuous video-EEG has the highest diagnostic yield within the first 24 hours and during the rewarming phase. In the absence of prior seizures or antiepileptic therapy, limiting continuous video-EEG to these periods in resource-limited settings may reduce cost during therapeutic hypothermia.