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1.
J Cell Sci ; 123(Pt 15): 2613-20, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20605922

RESUMO

In muscle cells, a complex network of Z-disc proteins allows proper reception, transduction and transmission of mechanical and biochemical signals. Mutations in genes encoding different Z-disc proteins such as integrin-linked kinase (ILK) and nexilin have recently been shown to cause heart failure by distinct mechanisms such as disturbed mechanosensing, altered mechanotransduction or mechanical Z-disc destabilization. We identified core-binding factor ß (CBFß) as an essential component for maintaining sarcomeric Z-disc and myofilament organization in heart and skeletal muscle. In CBFß-deficient cardiomyocytes and skeletal-muscle cells, myofilaments are thinned and Z-discs are misaligned, leading to progressive impairment of heart and skeletal-muscle function. Transcription of the gene encoding CBFß mainly depends on JunB activity. In JunB-morphant zebrafish, which show a heart-failure phenotype similar to that of CBFß-deficient zebrafish, transcript and protein levels of CBFß are severely reduced. Accordingly, ectopic expression of CBFß can reconstitute cardiomyocyte function and rescue heart failure in JunB morphants, demonstrating for the first time an essential role of JunB-CBFß signaling for maintaining sarcomere architecture and function.


Assuntos
Subunidade beta de Fator de Ligação ao Core/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Sarcômeros/metabolismo , Sequência de Aminoácidos , Animais , Subunidade beta de Fator de Ligação ao Core/química , Subunidade beta de Fator de Ligação ao Core/genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Humanos , Immunoblotting , Hibridização In Situ , Camundongos , Microscopia Eletrônica de Transmissão , Dados de Sequência Molecular , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestrutura , Miocárdio/metabolismo , Miocárdio/ultraestrutura , Miócitos Cardíacos/metabolismo , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-jun/genética , Sarcômeros/diagnóstico por imagem , Sarcômeros/genética , Homologia de Sequência de Aminoácidos , Ultrassonografia , Peixe-Zebra
2.
Basic Res Cardiol ; 106(1): 13-23, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20886220

RESUMO

MicroRNAs (miRNAs) are important regulators of adaptive and maladaptive responses in cardiovascular diseases and hence are considered to be potential therapeutical targets. However, their role as novel biomarkers for the diagnosis of cardiovascular diseases still needs to be systematically evaluated. We assessed here for the first time whole-genome miRNA expression in peripheral total blood samples of patients with acute myocardial infarction (AMI). We identified 121 miRNAs, which are significantly dysregulated in AMI patients in comparison to healthy controls. Among these, miR-1291 and miR-663b show the highest sensitivity and specificity for the discrimination of cases from controls. Using a novel self-learning pattern recognition algorithm, we identified a unique signature of 20 miRNAs that predicts AMI with even higher power (specificity 96%, sensitivity 90%, and accuracy 93%). In addition, we show that miR-30c and miR-145 levels correlate with infarct sizes estimated by Troponin T release. The here presented study shows that single miRNAs and especially miRNA signatures derived from peripheral blood, could be valuable novel biomarkers for cardiovascular diseases.


Assuntos
MicroRNAs/sangue , Infarto do Miocárdio/sangue , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Genoma Humano , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/etiologia , Sensibilidade e Especificidade , Troponina T/sangue
3.
Mol Cell Biol ; 31(16): 3424-35, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21670146

RESUMO

Integrin-linked kinase (ILK) is an essential component of the cardiac mechanical stretch sensor and is bound in a protein complex with parvin and PINCH proteins, the so-called ILK-PINCH-parvin (IPP) complex. We have recently shown that inactivation of ILK or ß-parvin activity leads to heart failure in zebrafish via reduced protein kinase B (PKB/Akt) activation. Here, we show that PINCH proteins localize at sarcomeric Z disks and costameres in the zebrafish heart and skeletal muscle. To investigate the in vivo role of PINCH proteins for IPP complex stability and PKB signaling within the vertebrate heart, we inactivated PINCH1 and PINCH2 in zebrafish. Inactivation of either PINCH isoform independently leads to instability of ILK, loss of stretch-responsive anf and vegf expression, and progressive heart failure. The predominant cause of heart failure in PINCH morphants seems to be loss of PKB activity, since PKB phosphorylation at serine 473 is significantly reduced in PINCH-deficient hearts and overexpression of constitutively active PKB reconstitutes cardiac function in PINCH morphants. These findings highlight the essential function of PINCH proteins in controlling cardiac contractility by granting IPP/PKB-mediated signaling.


Assuntos
Proteínas Musculares/fisiologia , Contração Miocárdica , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Proteínas de Peixe-Zebra/fisiologia , Animais , Insuficiência Cardíaca/etiologia , Músculo Esquelético , Miocárdio/química , Miocárdio/enzimologia , Fosforilação , Sarcômeros/química , Peixe-Zebra
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