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1.
Eur Heart J ; 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31004144

RESUMO

AIMS: Heart failure with preserved ejection fraction (HFpEF) and pathological cardiac aging share a complex pathophysiology, including extracellular matrix remodelling (EMR). Protease-activated receptor 2 (PAR2) deficiency is associated with EMR. The roles of PAR1 and PAR2 have not been studied in HFpEF, age-dependent cardiac fibrosis, or diastolic dysfunction (DD). METHODS AND RESULTS: Evaluation of endomyocardial biopsies from patients with HFpEF (n = 14) revealed that a reduced cardiac PAR2 expression was associated with aggravated DD and increased myocardial fibrosis (r = -0.7336, P = 0.0028). In line, 1-year-old PAR2-knockout (PAR2ko) mice suffered from DD with preserved systolic function, associated with an increased age-dependent α-smooth muscle actin expression, collagen deposition (1.7-fold increase, P = 0.0003), lysyl oxidase activity, collagen cross-linking (2.2-fold increase, P = 0.0008), endothelial activation, and inflammation. In the absence of PAR2, the receptor-regulating protein caveolin-1 was down-regulated, contributing to an augmented profibrotic PAR1 and transforming growth factor beta (TGF-ß)-dependent signalling. This enhanced TGF-ß/PAR1 signalling caused N-proteinase (ADAMTS3) and C-proteinase (BMP1)-related increased collagen I production from cardiac fibroblasts (CFs). PAR2 overexpression in PAR2ko CFs reversed these effects. The treatment with the PAR1 antagonist, vorapaxar, reduced cardiac fibrosis by 44% (P = 0.03) and reduced inflammation in a metabolic disease model (apolipoprotein E-ko mice). Patients with HFpEF with upstream PAR inhibition via FXa inhibitors (n = 40) also exhibited reduced circulating markers of fibrosis and DD compared with patients treated with vitamin K antagonists (n = 20). CONCLUSIONS: Protease-activated receptor 2 is an important regulator of profibrotic PAR1 and TGF-ß signalling in the heart. Modulation of the FXa/FIIa-PAR1/PAR2/TGF-ß-axis might be a promising therapeutic approach to reduce HFpEF.

2.
Circulation ; 139(15): 1813-1827, 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30700140

RESUMO

BACKGROUND: Titin is a giant elastic protein that spans the half-sarcomere from Z-disk to M-band. It acts as a molecular spring and mechanosensor and has been linked to striated muscle disease. The pathways that govern titin-dependent cardiac growth and contribute to disease are diverse and difficult to dissect. METHODS: To study titin deficiency versus dysfunction, the authors generated and compared striated muscle specific knockouts (KOs) with progressive postnatal loss of the complete titin protein by removing exon 2 (E2-KO) or an M-band truncation that eliminates proper sarcomeric integration, but retains all other functional domains (M-band exon 1/2 [M1/2]-KO). The authors evaluated cardiac function, cardiomyocyte mechanics, and the molecular basis of the phenotype. RESULTS: Skeletal muscle atrophy with reduced strength, severe sarcomere disassembly, and lethality from 2 weeks of age were shared between the models. Cardiac phenotypes differed considerably: loss of titin leads to dilated cardiomyopathy with combined systolic and diastolic dysfunction-the absence of M-band titin to cardiac atrophy and preserved function. The elastic properties of M1/2-KO cardiomyocytes are maintained, while passive stiffness is reduced in the E2-KO. In both KOs, we find an increased stress response and increased expression of proteins linked to titin-based mechanotransduction (CryAB, ANKRD1, muscle LIM protein, FHLs, p42, Camk2d, p62, and Nbr1). Among them, FHL2 and the M-band signaling proteins p62 and Nbr1 are exclusively upregulated in the E2-KO, suggesting a role in the differential pathology of titin truncation versus deficiency of the full-length protein. The differential stress response is consistent with truncated titin contributing to the mechanical properties in M1/2-KOs, while low titin levels in E2-KOs lead to reduced titin-based stiffness and increased strain on the remaining titin molecules. CONCLUSIONS: Progressive depletion of titin leads to sarcomere disassembly and atrophy in striated muscle. In the complete knockout, remaining titin molecules experience increased strain, resulting in mechanically induced trophic signaling and eventually dilated cardiomyopathy. The truncated titin in M1/2-KO helps maintain the passive properties and thus reduces mechanically induced signaling. Together, these findings contribute to the molecular understanding of why titin mutations differentially affect cardiac growth and have implications for genotype-phenotype relations that support a personalized medicine approach to the diverse titinopathies.

3.
PLoS One ; 13(6): e0198492, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29889873

RESUMO

Diastolic dysfunction is increasingly prevalent in our ageing society and an important contributor to heart failure. The giant protein titin could serve as a therapeutic target, as its elastic properties are a main determinant of cardiac filling in diastole. This study aimed to develop a high throughput pharmacological screen to identify small molecules that affect titin isoform expression through differential inclusion of exons encoding the elastic PEVK domains. We used a dual luciferase splice reporter assay that builds on the titin splice factor RBM20 to screen ~34,000 small molecules and identified several compounds that inhibit the exclusion of PEVK exons. These compounds belong to the class of cardenolides and affect RBM20 dependent titin exon exclusion but did not affect RBFOX1 mediated splicing of FMNL3. We provide evidence that cardenolides do not bind to the RNA interacting domain of RBM20, but reduce RBM20 protein levels and alter transcription of select splicing factors that interact with RBM20. Cardenolides affect titin isoform expression. Understanding their mode of action and harnessing the splice effects through chemical modifications that suppress the effects on ion homeostasis and more selectively affect cardiac splicing has the potential to improve cardiac filling and thus help patients with diastolic heart failure, for which currently no targeted therapy exists.

4.
Science ; 356(6335): 307-311, 2017 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-28428423

RESUMO

The African naked mole-rat's (Heterocephalus glaber) social and subterranean lifestyle generates a hypoxic niche. Under experimental conditions, naked mole-rats tolerate hours of extreme hypoxia and survive 18 minutes of total oxygen deprivation (anoxia) without apparent injury. During anoxia, the naked mole-rat switches to anaerobic metabolism fueled by fructose, which is actively accumulated and metabolized to lactate in the brain. Global expression of the GLUT5 fructose transporter and high levels of ketohexokinase were identified as molecular signatures of fructose metabolism. Fructose-driven glycolytic respiration in naked mole-rat tissues avoids feedback inhibition of glycolysis via phosphofructokinase, supporting viability. The metabolic rewiring of glycolysis can circumvent the normally lethal effects of oxygen deprivation, a mechanism that could be harnessed to minimize hypoxic damage in human disease.


Assuntos
Adaptação Fisiológica , Anaerobiose , Encéfalo/fisiologia , Frutose/metabolismo , Glicólise , Ratos-Toupeira/metabolismo , Oxigênio/metabolismo , Animais , Encéfalo/metabolismo , Frutoquinases/metabolismo , Transportador de Glucose Tipo 5/metabolismo , Ácido Láctico/metabolismo , Camundongos , Miocárdio/metabolismo , Sacarose/metabolismo
5.
J Mol Med (Berl) ; 94(12): 1349-1358, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27889803

RESUMO

Impaired diastolic filling is a main contributor to heart failure with preserved ejection fraction (HFpEF), a syndrome with increasing prevalence and no treatment. Both collagen and the giant sarcomeric protein titin determine diastolic function. Since titin's elastic properties can be adjusted physiologically, we evaluated titin-based stiffness as a therapeutic target. We adjusted RBM20-dependent cardiac isoform expression in the titin N2B knockout mouse with increased ventricular stiffness. A ~50 % reduction of RBM20 activity does not only maintain cardiac filling in diastole but also ameliorates cardiac atrophy and thus improves cardiac function in the N2B-deficient heart. Reduced RBM20 activity partially normalized gene expression related to muscle development and fatty acid metabolism. The adaptation of cardiac growth was related to hypertrophy signaling via four-and-a-half lim-domain proteins (FHLs) that translate mechanical input into hypertrophy signals. We provide a novel link between cardiac isoform expression and trophic signaling via FHLs and suggest cardiac splicing as a therapeutic target in diastolic dysfunction. KEY MESSAGE: Increasing the length of titin isoforms improves ventricular filling in heart disease. FHL proteins are regulated via RBM20 and adapt cardiac growth. RBM20 is a therapeutic target in diastolic dysfunction.


Assuntos
Cardiomegalia/metabolismo , Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/metabolismo , Proteínas Quinases/genética , Proteínas de Ligação a RNA/genética , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Colágeno/genética , Colágeno/metabolismo , Diástole/fisiologia , Regulação da Expressão Gênica , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Ventrículos do Coração/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Proteínas Quinases/deficiência , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Volume Sistólico/fisiologia
6.
J Cell Sci ; 127(Pt 17): 3666-74, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-24982444

RESUMO

Cardiac titin is the main determinant of sarcomere stiffness during diastolic relaxation. To explore whether titin stiffness affects the kinetics of cardiac myofibrillar contraction and relaxation, we used subcellular myofibrils from the left ventricles of homozygous and heterozygous N2B-knockout mice which express truncated cardiac titins lacking the unique elastic N2B region. Compared with myofibrils from wild-type mice, myofibrils from knockout and heterozygous mice exhibit increased passive myofibrillar stiffness. To determine the kinetics of Ca(2+)-induced force development (rate constant kACT), myofibrils from knockout, heterozygous and wild-type mice were stretched to the same sarcomere length (2.3 µm) and rapidly activated with Ca(2+). Additionally, mechanically induced force-redevelopment kinetics (rate constant kTR) were determined by slackening and re-stretching myofibrils during Ca(2+)-mediated activation. Myofibrils from knockout mice exhibited significantly higher kACT, kTR and maximum Ca(2+)-activated tension than myofibrils from wild-type mice. By contrast, the kinetic parameters of biphasic force relaxation induced by rapidly reducing [Ca(2+)] were not significantly different among the three genotypes. These results indicate that increased titin stiffness promotes myocardial contraction by accelerating the formation of force-generating cross-bridges without decelerating relaxation.


Assuntos
Conectina/metabolismo , Relaxamento Muscular/fisiologia , Contração Miocárdica/fisiologia , Miofibrilas/metabolismo , Sarcômeros/metabolismo , Deleção de Sequência/genética , Animais , Sequência de Bases/genética , Cálcio/metabolismo , Conectina/genética , Cinética , Camundongos , Contração Miocárdica/genética , Miocárdio/metabolismo , Miofibrilas/fisiologia
7.
J Clin Invest ; 124(8): 3419-30, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24960161

RESUMO

Mutations in the gene encoding the RNA-binding protein RBM20 have been implicated in dilated cardiomyopathy (DCM), a major cause of chronic heart failure, presumably through altering cardiac RNA splicing. Here, we combined transcriptome-wide crosslinking immunoprecipitation (CLIP-seq), RNA-seq, and quantitative proteomics in cell culture and rat and human hearts to examine how RBM20 regulates alternative splicing in the heart. Our analyses revealed the presence of a distinct RBM20 RNA-recognition element that is predominantly found within intronic binding sites and linked to repression of exon splicing with RBM20 binding near 3' and 5' splice sites. Proteomic analysis determined that RBM20 interacts with both U1 and U2 small nuclear ribonucleic particles (snRNPs) and suggested that RBM20-dependent splicing repression occurs through spliceosome stalling at complex A. Direct RBM20 targets included several genes previously shown to be involved in DCM as well as genes not typically associated with this disease. In failing human hearts, reduced expression of RBM20 affected alternative splicing of several direct targets, indicating that differences in RBM20 expression may affect cardiac function. Together, these findings identify RBM20-regulated targets and provide insight into the pathogenesis of human heart failure.


Assuntos
Processamento Alternativo , Miocárdio/metabolismo , Precursores de RNA/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Sequência de Bases , Sítios de Ligação/genética , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/metabolismo , Estudos de Coortes , Éxons , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Humanos , Mutação , Miócitos Cardíacos/metabolismo , Precursores de RNA/genética , Processamento Pós-Transcricional do RNA , Sítios de Splice de RNA , Proteínas de Ligação a RNA/genética , Ratos , Ratos Sprague-Dawley , Ribonucleoproteína Nuclear Pequena U1/metabolismo , Ribonucleoproteína Nuclear Pequena U2/metabolismo , Seleção Genética , Spliceossomos/metabolismo
8.
Nat Med ; 18(5): 766-73, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22466703

RESUMO

Alternative splicing has a major role in cardiac adaptive responses, as exemplified by the isoform switch of the sarcomeric protein titin, which adjusts ventricular filling. By positional cloning using a previously characterized rat strain with altered titin mRNA splicing, we identified a loss-of-function mutation in the gene encoding RNA binding motif protein 20 (Rbm20) as the underlying cause of pathological titin isoform expression. The phenotype of Rbm20-deficient rats resembled the pathology seen in individuals with dilated cardiomyopathy caused by RBM20 mutations. Deep sequencing of the human and rat cardiac transcriptome revealed an RBM20-dependent regulation of alternative splicing. In addition to titin (TTN), we identified a set of 30 genes with conserved splicing regulation between humans and rats. This network is enriched for genes that have previously been linked to cardiomyopathy, ion homeostasis and sarcomere biology. Our studies emphasize the key role of post-transcriptional regulation in cardiac function and provide mechanistic insights into the pathogenesis of human heart failure.


Assuntos
Cardiomiopatia Dilatada/genética , Proteínas Musculares/genética , Proteínas Quinases/genética , Processamento de RNA , Proteínas de Ligação a RNA/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Sequência de Bases , Conectina , Humanos , Proteínas com Domínio LIM/genética , Dados de Sequência Molecular , Mutação , Proteínas de Ligação a RNA/fisiologia , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos F344
9.
J Mol Cell Cardiol ; 51(3): 428-34, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21708170

RESUMO

Viscosity is proposed to modulate diastolic function, but only limited understanding of the source(s) of viscosity exists. In vitro experiments have shown that the proline-glutamic acid-valine-lysine (PEVK) rich element of titin interacts with actin, causing a viscous force in the sarcomere. It is unknown whether this mechanism contributes to viscosity in vivo. We tested the hypothesis that PEVK-actin interaction causes cardiac viscosity and is important in vivo via an integrative physiological study on a unique PEVK knockout (KO) model. Both skinned cardiomyocytes and papillary muscle fibers were isolated from wildtype (WT) and PEVK KO mice and passive viscosity was examined using stretch-hold-release and sinusoidal analysis. Viscosity was reduced by ~60% in KO myocytes and ~50% in muscle fibers at room temperature. The PEVK-actin interaction was not modulated by temperature or diastolic calcium, but was increased by lattice compression. Stretch-hold and sinusoidal frequency protocols on intact isolated mouse hearts showed a smaller, 30-40% reduction in viscosity, possibly due to actomyosin interactions, and showed that microtubules did not contribute to viscosity. Transmitral Doppler echocardiography similarly revealed a 40% decrease in LV chamber viscosity in the PEVK KO in vivo. This integrative study is the first to quantify the influence of a specific molecular (PEVK-actin) viscosity in vivo and shows that PEVK-actin interactions are an important physiological source of viscosity.


Assuntos
Actinas/metabolismo , Ventrículos do Coração/metabolismo , Proteínas Musculares/metabolismo , Proteínas Quinases/metabolismo , Actomiosina/antagonistas & inibidores , Animais , Conectina , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Masculino , Camundongos , Camundongos Knockout , Proteínas Musculares/genética , Miocárdio/metabolismo , Ligação Proteica/genética , Proteínas Quinases/genética , Sarcômeros/genética , Sarcômeros/metabolismo , Viscosidade/efeitos dos fármacos
10.
J Cell Biol ; 193(4): 785-98, 2011 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-21555460

RESUMO

The giant muscle protein titin is an essential structural component of the sarcomere. It forms a continuous periodic backbone along the myofiber that provides resistance to mechanical strain. Thus, the titin filament has been regarded as a blueprint for sarcomere assembly and a prerequisite for stability. Here, a novel titin-eGFP knockin mouse provided evidence that sarcomeric titin is more dynamic than previously suggested. To study the mobility of titin in embryonic and neonatal cardiomyocytes, we used fluorescence recovery after photobleaching and investigated the contribution of protein synthesis, contractility, and calcium load to titin motility. Overall, the kinetics of lateral and longitudinal movement of titin-eGFP were similar. Whereas protein synthesis and developmental stage did not alter titin dynamics, there was a strong, inhibitory effect of calcium on titin mobility. Our results suggest a model in which the largely unrestricted movement of titin within and between sarcomeres primarily depends on calcium, suggesting that fortification of the titin filament system is activity dependent.


Assuntos
Proteínas Musculares/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Quinases/metabolismo , Sarcômeros/metabolismo , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , Células Cultivadas , Conectina , Recuperação de Fluorescência Após Fotodegradação , Imunofluorescência , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Cinética , Camundongos , Camundongos da Linhagem 129 , Camundongos Transgênicos , Microscopia de Vídeo , Proteínas Musculares/genética , Proteínas Quinases/genética , Transporte Proteico , Proteínas Recombinantes de Fusão/metabolismo
11.
Circ Res ; 105(6): 557-64, 2009 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-19679835

RESUMO

RATIONALE: The giant protein titin plays key roles in myofilament assembly and determines the passive mechanical properties of the sarcomere. The cardiac titin molecule has 2 mayor elastic elements, the N2B and the PEVK region. Both have been suggested to determine the elastic properties of the heart with loss of function data only available for the N2B region. OBJECTIVE: The purpose of this study was to investigate the contribution of titin's proline-glutamate-valine-lysine (PEVK) region to biomechanics and growth of the heart. METHODS AND RESULTS: We removed a portion of the PEVK segment (exons 219 to 225; 282 aa) that corresponds to the PEVK element of N2B titin, the main cardiac titin isoform. Adult homozygous PEVK knockout (KO) mice developed diastolic dysfunction, as determined by pressure-volume loops, echocardiography, isolated heart experiments, and muscle mechanics. Immunoelectron microscopy revealed increased strain of the N2B element, a spring region retained in the PEVK-KO. Interestingly, the PEVK-KO mice had hypertrophied hearts with an induction of the hypertrophy and fetal gene response that includes upregulation of FHL proteins. This contrasts the cardiac atrophy phenotype with decreased FHL2 levels that result from the deletion of the N2B element. CONCLUSIONS: Titin's PEVK region contributes to the elastic properties of the cardiac ventricle. Our findings are consistent with a model in which strain of the N2B spring element and expression of FHL proteins trigger cardiac hypertrophy. These novel findings provide a molecular basis for the future differential therapy of isolated diastolic dysfunction versus more complex cardiomyopathies.


Assuntos
Cardiomiopatia Hipertrófica/metabolismo , Ventrículos do Coração/metabolismo , Proteínas Musculares/metabolismo , Proteínas Quinases/metabolismo , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/metabolismo , Sequência de Aminoácidos/genética , Animais , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/fisiopatologia , Conectina , Elasticidade , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/ultraestrutura , Camundongos , Camundongos Knockout , Proteínas Musculares/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Quinases/genética , Estrutura Terciária de Proteína/genética , Sarcômeros/genética , Sarcômeros/metabolismo , Sarcômeros/ultraestrutura , Deleção de Sequência/genética
12.
J Exp Med ; 205(10): 2369-79, 2008 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-18794341

RESUMO

The Coxsackievirus-adenovirus receptor (CAR) is known for its role in virus uptake and as a protein of the tight junction. It is predominantly expressed in the developing brain and heart and reinduced upon cardiac remodeling in heart disease. So far, the physiological functions of CAR in the adult heart are largely unknown. We have generated a heart-specific inducible CAR knockout (KO) and found impaired electrical conduction between atrium and ventricle that increased with progressive loss of CAR. The underlying mechanism relates to the cross talk of tight and gap junctions with altered expression and localization of connexins that affect communication between CAR KO cardiomyocytes. Our results indicate that CAR is not only relevant for virus uptake and cardiac remodeling but also has a previously unknown function in the propagation of excitation from the atrium to the ventricle that could explain the association of arrhythmia and Coxsackievirus infection of the heart.


Assuntos
Comunicação Celular/fisiologia , Sistema de Condução Cardíaco/fisiologia , Receptores Virais/metabolismo , Junções Íntimas/metabolismo , Animais , Nó Atrioventricular/fisiologia , Caderinas/genética , Caderinas/metabolismo , Células Cultivadas , Conexina 43/genética , Conexina 43/metabolismo , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus , Infecções por Coxsackievirus/metabolismo , Infecções por Coxsackievirus/fisiopatologia , Eletrocardiografia , Eletrofisiologia , Junções Comunicantes/metabolismo , Coração/anatomia & histologia , Coração/embriologia , Coração/crescimento & desenvolvimento , Coração/fisiologia , Sistema de Condução Cardíaco/anatomia & histologia , Humanos , Camundongos , Camundongos Knockout , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Fenótipo , Receptores Virais/genética
13.
Proc Natl Acad Sci U S A ; 104(9): 3444-9, 2007 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-17360664

RESUMO

Titin is a giant protein that is in charge of the assembly and passive mechanical properties of the sarcomere. Cardiac titin contains a unique N2B region, which has been proposed to modulate elasticity of the titin filament and to be important for hypertrophy signaling and the ischemic stress response through its binding proteins FHL2 and alphaB-crystallin, respectively. To study the role of the titin N2B region in systole and diastole of the heart, we generated a knockout (KO) mouse deleting only the N2B exon 49 and leaving the remainder of the titin gene intact. The resulting mice survived to adulthood and were fertile. Although KO hearts were small, they produced normal ejection volumes because of an increased ejection fraction. FHL2 protein levels were significantly reduced in the KO mice, a finding consistent with the reduced size of KO hearts. Ultrastructural analysis revealed an increased extension of the remaining spring elements of titin (tandem Ig segments and the PEVK region), which, together with the reduced sarcomere length and increased passive tension derived from skinned cardiomyocyte experiments, translates to diastolic dysfunction as documented by echocardiography. We conclude from our work that the titin N2B region is dispensable for cardiac development and systolic properties but is important to integrate trophic and elastic functions of the heart. The N2B-KO mouse is the first titin-based model of diastolic dysfunction and, considering the high prevalence of diastolic heart failure, it could provide future mechanistic insights into the disease process.


Assuntos
Cardiomiopatias/genética , Diástole , Proteínas Musculares/genética , Miocárdio/patologia , Proteínas Quinases/genética , Sarcômeros/metabolismo , Deleção de Sequência/genética , Animais , Atrofia/patologia , Western Blotting , Cardiomiopatias/metabolismo , Conectina , Ecocardiografia , Eletroforese em Gel de Poliacrilamida , Éxons/genética , Imunofluorescência , Proteínas de Homeodomínio/metabolismo , Proteínas com Homeodomínio LIM , Camundongos , Camundongos Knockout , Microscopia Imunoeletrônica , Proteínas Musculares/metabolismo , Proteínas Musculares/ultraestrutura , Proteínas Quinases/metabolismo , Proteínas Quinases/ultraestrutura , Sarcômeros/patologia , Fatores de Transcrição/metabolismo
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