In cell culture, entry into mitosis of many adherent mammalian cells is accompanied by substantial changes in cellular architecture. Flat, spread-out interphase cells detach from the extracellular matrix and become more spherical. These changes in cell shape are mediated by rearrangements in the actin cytoskeleton, a dynamic network of actin filaments that are organized by actin-binding proteins. Filamin A (FLNa) is a 280 kD actin-binding protein that crosslinks actin filaments into parallel bundles or three-dimensional orthogonal networks. We previously identified FLNa as an in vitro substrate of cyclin-dependent kinase 1 (Cdk1), a kinase that regulates entry into mitosis, and hypothesized that Cdk1 phosphorylation of FLNa regulates mitotic actin remodelling. Using mass spectrometry and a p-FLNa antibody, we show that FLNa is phosphorylated in vivo in HeLa cells on multiple Cdk1 sites, including serines 1084, 1459 and 1533. All three sites match the phosphorylation consensus sequence of Cdk1. We further show that p-FLNa is almost fully dephosphorylated by anaphase, consistent with it being a cell cycle-regulated substrate. Using a phospho-specific antibody, we find that p-FLNa has decreased cortical actin localization compared to total FLNa in mitotic cells. To investigate the functional role of mitotic FLNa phosphorylation, we mutated serines 1084, 1459 and 1533 to nonphosphorylatable alanine and expressed this FLNa mutant (FLNa-S1084A, S1459A, S1533A, referred to as “FLNa-AAA GFP”) in FLNa-deficient human M2 melanoma cells. FLNa-AAA GFP-expressing cells have enhanced FLNa-AAA GFP localization at sites of contact between daughter cells and this correlates with defects in cell division and impaired cell migration. Therefore, mitotic delocalization of cortical FLNa is critical for successful cell division and interphase cell behaviour.

Injectable biomaterials have emerged as a treatment for myocardial infarction (MI). They can be applied either as an enhancement for cell therapy or as a stand-alone treatment for MI. The main focus of this study was to apply circulating angiogenic cells (CACs) with or without an injectable collagen matrix for MI treatment in a mouse model. Furthermore, a collagen-chitosan matrix was tested for modulating the myocardial maladaptive remodeling post-MI. First, the in vivo thermo-gelling and retention properties of the collagen matrix were validated using positron emission tomography (PET) tracer and quantum dot (Qdot) labelled matrix in MI mouse hearts. The therapeutic potential of the matrix ± CACs was then tested in a mouse MI model. The results showed that CACs-only and matrix-only treatments were associated with cardiac function preservation. However, in combination, CAC + matrix therapy had a synergistic effect and significantly improved cardiac function (echocardiography), perfusion and viability (PET scan), increased cell engraftment and arteriole density, and reduced the infarct size. CAC-matrix interaction through the integrin alpha2 receptor was essential for the observed therapeutic effect. In a third study, the addition of chitosan (a polysaccharide) to the collagen matrix was shown to reduce maladaptive remodeling post-MI by limiting cardiac fibroblast-to-myofibroblast differentiation and scar formation. In conclusion, these collagen-based hydrogels hold promise to enhance cardiac repair as a delivery scaffold for therapeutic cells, and/or as a stand-alone treatment, which can actively modulate the environment including the fibrotic process after MI.

L'enseignement de la philosophie, dans les lycées chiliens et français a su défendre sa place au sein de l'enseignement secondaire malgré l'intervention des politiques libérales et néolibérales qui ont envahi l'éducation. Cela a été un succès, mais la question devient: quelle philosophie a-t-on voulu défendre? Pourquoi faire? Ce sont aussi ces questions que s'est posé Jacques Derrida dans les années soixante-dix aux fin de mettre en pratique et systématiser le travail théorique qu'il avait fait à partir de la publication de: De la Grammatologie en 1967. Dans cette recherche nous essayerons de répondre à ces questions à partir du travail réalisé par Derrida dans les années 1967 et 1978. Nous considérons que cette période  propédeutique  nous permet de démontrer que la déconstruction aurait comme base stratégique l'enseignement philosophique. C'est à partir de cette prémisse que nous espérons pouvoir établir quelques idées régulatrices déconstructives qui justifient la présence de la philosophie dans le secondaire. Elles seraient nécessaires et fondamentales pour construire un cadre philosophique référentiel et de cette façon, créer des stratégies d'enseignement propres aux conditions historiques, géographiques et culturelles des jeunes. Ces fondements seraient la base principale de la possibilité de déconstruction – la lutte et la résistance – de l'institution de la philosophie. / Although secundary education, both Chilean and French education, has not been unaware to the risk that philosophy has run with the intervention of the liberal and neoliberal policies in education, the multiple edges that build its institutional framework have been able to defend and, therefore, maintain the teaching to adolescents. This has certainly been an achievement, but, what philosofy has defended itself? For what? These interrogatives are also some of which Jaques Derrida contemplated in the seventies, with the idea of putting into practice and systematize the theoretical work that he had been doing since the publication of Of Grammatology in 1967.In this research, we attempt to answer these interrogatives from Derrida’s work, done between 1967 and 1968. We consider that this period – which is institutive– allows us to demonstrate that deconstruction would have the philosophical basis as strategic teaching. From the deconstructive premise, we intend to establish certain guidelines to justify the presence of philosophy in high school, needed to generate a referential philosophical framework and create future strategies of teaching philosophy, distinctive of historical, geographical and cultural conditions of the adolescents and which are the fundamental basis of the possibility of deconstruction -resistance and struggle- of the philosophical institution. / A pesar que la enseñanza secundaria, tanto la chilena como la francesa, no ha estado ajena al riesgo que ha corrido la filosofía con la intervención de políticas liberales y neoliberales en la educación, las múltiples aristas que constituyen su entramado institucional, han sabido defender y, por lo tanto, mantener la enseñanza de la filosofía para los jóvenes. Sin duda que esto ha sido un logro, pero ¿qué filosofía se ha defendido? ¿Para qué? Estas preguntas son también algunas de las cuales se planteó Jacques Derrida en los años setenta con la idea de poner en práctica y de sistematizar el trabajo teórico que venía haciendo desde la publicación de De la gramatología en 1967. En esta investigación intentamos responder estas interrogantes a partir del trabajo realizado por Derrida entre los años 1967 y 1978. Consideramos queeste período −que es instituyente− nos permite demostrar que la deconstrucción tendría como base estratégica la enseñanza filosófica. A partir de esta premisa pretendemos establecer ciertos lineamientos deconstructivos que justifiquen la presencia de la filosofía en secundaria, necesarios para generar un marco filosófico referencial y para crear futuras estrategias de enseñanza de la filosofía que sean propias a las condiciones históricas, geográficas y culturalesde los jóvenes, base fundamental de la posibilidad de deconstrucción −resistencia y lucha− de la institución filosófica.

La contraction cardiaque nécessite un apport énergétique important, dont la source principale est l'oxydation des acides gras dans la mitochondrie. Ces acides gras pénètrent dans la mitochondrie sous la forme d'acyl-carnitine. Lors du couplage excitation-contraction, il y a une communication entre la contraction et le métabolisme assurée par les variations de potentiel et les variations calciques concomitantes. Cette communication permet d'adapter la quantité d'énergie synthétisée en fonction des besoins contractiles. Des observations cliniques et expérimentales indiquent que le métabolisme module également les mécanismes de contraction. En effet de fortes modifications de la balance énergétique observée lors de pathologie comme le syndrome métabolique ou le déficit primaire en carnitine induisent des dysfonctions contractiles et des troubles du rythme cardiaque. L'homéostasie mitochondriale semble tenir un rôle important dans cette communication, mais les mécanismes impliqués restent encore mal connus. Dans ce travail nous nous sommes intéressés à comprendre les comment de fortes variations d'acyl-carnitine influencent l'apparition de troubles du rythme et participent au remodelage ventriculaire. Lors d'une approche intégrative nous avons mis en évidence le rôle central de l'adenine nucleotide transporteur (ANT) dans la genèse des troubles du rythme induit par une forte concentration en palmitoyl-carnitine. De plus des études in vivo sur des animaux déficients en carnitine, ont permis de décrire pour la première fois une relation entre une diminution de l'intervalle QT (QT court) avec un désordre métabolique. / Heart contraction requires a considerable amount of energy. Mitochondrial fatty acid oxidation is the major source of energy production in the heart. Fatty acids diffuse through the mitochondrial membrane in the acyl-carnitine form. During excitation-contraction coupling, variations of membrane potential and calcium concentration allow the communication between contraction and metabolism. This communication allows the adaption of energy production into contractile function. Clinical and experimental observations indicate that metabolism modulates contraction mechanisms. In particular, the energetic imbalance observed in metabolic syndrome or primary carnitine deficiency induces a contractile disturbance and arrhythmias. Mitochondrial homeostasis seems to be an important participant though the mechanisms involved in this phenomenon remain to be completely elucidated. In this study, we examined the influence of acylcarnitine concentration variations on cardiac rhythm and ventricular remodeling. Through an integrative approach, we have demonstrated the pivotal role of the adenine nucleotide transporter (ANT) in the apparition of high acylcarnitine concentration associated arrhythmia. Furthermore, in vivo studies with carnitine deficient mice reveal, for the first time, a relationship between the QT interval duration (short QT) and metabolic disturbance.

Hydrogen sulfide (H2S) is a gasotransmitter that has shown cardioprotective effects in the setting of myocardial injury such as acute myocardial infarction (MI) and pressure overload-induced heart failure. However, there are shortcomings in precision and control release from the use of traditional formulations of H2S in the form of inorganic salts. In this thesis, we sought to determine if the novel, orally active, slow-releasing H2S-compound SG1002 plays a role in attenuating MI-induced left ventricular (LV) dysfunction and adverse remodeling. We also evaluated the effect of SG1002 on changes in ECG parameters such as QT interval, in addition to 28-day survival post MI. SG1002 protects against ischemic cardiomyopathy in mice by mitigating LV dysfunction as measured by echocardiography and decreasing LV scar size as measured by histopathological methods. The improvement in survival might be due to the reduction in QT interval prolongation hence lessening the likelihood of forming lethal arrhythmias post MI. Western blot analyses of SG1002 treated mice showed restoration of VEGF levels indicating a pivotal role played by pro-angiogenic signaling in the improvement of cardiac function and attenuation of adverse remodeling. We propose that SG1002 can be a promising pharmacotherapeutic means for the treatment of ischemic heart failure.

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2018-06-21T18:29:06Z No. of bitstreams: 1 Eduardo Tadeu Santana.pdf: 3781492 bytes, checksum: 5fb6eff774c2c39d42bab565b9e807ef (MD5) / Made available in DSpace on 2018-06-21T18:29:06Z (GMT). No. of bitstreams: 1 Eduardo Tadeu Santana.pdf: 3781492 bytes, checksum: 5fb6eff774c2c39d42bab565b9e807ef (MD5) Previous issue date: 2015-12-18 / The ligation of the anterior descending coronary artery is the most commonly used experimental model to induce myocardial infarction (MI) in rodents. A high mortality in the acute phase and the heterogeneity of the size of the MI obtained are drawbacks recognized in this model. In an attempt to solve the problem, our group recently developed a new MI experimental model which is based on application of myocardial ablation radio-frequency currents (AB-RF) that yielded MI with homogeneous sizes and significantly reduce acute mortality. In addition, cardiac structural and functional changes aroused by AB-RF were similar to those seen in animals with MI induced by coronary artery ligation. Herein, we evaluated modifications of gene expression that govern post-MI milieu in occlusion and ablation models. We analyzed 48 mRNA expressions of 9 different signal transduction pathways (signs of cell survival and metabolism, matrix extracellular, cell cycle, oxidative stress, apoptosis, calcium signaling, hypertrophy markers, angiogenesis and inflammation) in rat left ventricle 1 week after MI promoted by either coronary occlusion and AB-RF. Furthermore, high-throughput miRNA analysis was also assessed after either MI procedures. Interestingly, mRNA expression levels and miRNA expressions were similar in both models after MI, with few specificities in each model. This study reports for the first time the global changes in rat cardiac mRNA and miRNA contents after two different MI procedures and identifies key signaling regulators modulating the pathophysiology of these two models that might culminate in heart failure. Furthermore, these analyses would enhance our present knowledge regarding altered pathophysiology of these two different MI models. / A ligadura da artéria coronariana descendente anterior é o modelo experimental mais comumente usado para induzir o infarto do miocárdio (IM) em roedores. Entretanto, uma elevada taxa de mortalidade na fase aguda e a heterogeneidade do tamanho do IM obtidos são desvantagens reconhecidas neste modelo. Em uma tentativa de resolver o problema, o nosso grupo desenvolveu recentemente um novo modelo experimental de insuficiência cardíaca que se baseia na aplicação de correntes de radiofrequência ablação do miocárdio (AB-RF), produzindo IM com tamanhos homogêneos e com significativamente redução da mortalidade aguda. Além disso, alterações estruturais e funcionais do coração deste modelo foram semelhantes aos observados em animais com infarto induzido por ligação da artéria coronária. Aqui, nós avaliamos modificações da expressão de RNA mensageiro (RNAm) de genes após IM induzido por oclusão e ablação. Foram analisadas as expressões de 48 RNAm de 9 diferentes vias de transdução de sinal (sinais de sobrevivência celular e metabolismo, matriz extracelular, ciclo celular, estresse oxidativo, apoptose, sinalização de cálcio, marcadores de hipertrofia, angiogênese e inflamação) no ventrículo esquerdo de ratos uma semana após o IM promovido por oclusão coronária e AB-RF. Além disso, a análise de alto rendimento de miRNA também foi avaliada após ambos procedimentos de IM. Curiosamente, os níveis de expressão de RNAm e expressão de miRNA foram semelhantes em ambos os modelos após o IM, com algumas especificidades em cada modelo. Este estudo relata pela primeira vez as mudanças globais nos conteúdos de RNAm e miRNA após dois procedimentos de IM diferentes e identifica reguladores que podem modular a fisiopatologia desses dois modelos, culminando em insuficiência cardíaca.

A simpatectomia é uma modalidade terapêutica ampla e consagrada há décadas para determinadas patologias. Recentemente, alguns trabalhos sugerem a aplicação de tal técnica no tratamento da insuficiência cardíaca. Contudo, seus efeitos fisiológicos cardíacos em modelos experimentais foram pouco estudados. O objetivo deste trabalho é avaliar os efeitos fisiológicos da simpatectomia no coração. Para tal, foi utilizado o modelo experimental de simpatectomia em ratos pela técnica de esclerose do gânglio estrelado por punção e injeção de álcool absoluto. O estudo avaliou cinco grupos: controle (15 animais), simpatectomia unilateral esquerda (15 animais), simpatectomia bilateral (31 animais), simpatectomia unilateral esquerda com atenolol (15 animais) e atenolol sem simpatectomia (15 animais). Foram avaliadas as variáveis relacionadas ao sistema nervoso autônomo, como propriedades cronotrópicas em repouso e ao esforço, modulação autonômica cardiovascular, catecolaminas miocárdicas e periféricas e receptores beta-adrenérgicos do miocárdio. Também foram analisados os efeitos na função ventricular e no tamanho do miócito. As variáveis propostas para análise foram obtidas por ECG de repouso, ecocardiograma, teste de esforço máximo, frequência cardíaca ao esforço e variabilidade da FC e da PAS avaliadas no domínio do tempo e da frequência. As informações do miocárdio quanto a receptores, catecolaminas miocárdicas, catecolaminas periféricas e tamanho dos miócitos foram obtidas por PCR, ELISA, HPLC e morfometria do miócito, respectivamente. Este estudo evidenciou que os animais do grupo bilateral apresentam maiores níveis de catecolaminas periféricas e, consequentemente, são mais taquicárdicos e hipertensos. Os achados sugerem a ativação, neste grupo, de uma via compensatória que pode ter efeitos deletérios / Sympathectomy is a therapeutic modality used to treat certain diseases during decades. Recently, some studies suggest the application of this technique in the treatment of heart failure. However, its physiological effects upon the heart have been slightly studied. The objective of this study was to evaluate the physiological effects of sympathectomy in the heart. For this purpose, we used the experimental model of sympathectomy in rats by stellate ganglion sclerosis technique starring puncture and absolute alcohol injection. The study evaluated five groups of wistar rats: control (15), left unilateral sympathectomy (15), bilateral sympathectomy (31), left unilateral sympathectomy with atenolol (15) and atenolol without sympathectomy (15). We assessed variables related to the autonomic nervous system, such as chronotropic properties at rest and stress, cardiovascular autonomic modulation, myocardial and peripheral catecholamines and beta-adrenergic receptors in the myocardium. As well, we studied the effects on ventricular function and myocyte size. The proposed variables for analysis were obtained by resting electrocardiogram, echocardiography, maximal exercise test, heart rate at exercise and heart rate and systolic blood pressure variability in the time and frequency domain. The myocardial receptors, myocardial and peripheral catecholamines and myocyte size were obtained by PCR, ELISA, HPLC and myocyte morphometry, respectively. This study showed that the animals in the bilateral group had higher levels of peripheral catecholamine and, consequently, a higher heart rate and blood pressure. These findings suggest the activation of a compensatory pathway in the sympathectomy group that may have deleterious effects

O infarto agudo do miocárdio (IAM) é a principal causa de mortalidade mundial. O IAM é acompanhado de remodelamento cardíaco, caracterizado por alterações gênicas, moleculares e celulares, com consequentes alterações no tamanho, forma e função do coração, e resultante disfunção ventricular e insuficiência cardíaca. Evidências experimentais e clínicas indicam que a prevenção ou o tratamento do remodelamento cardíaco beneficiam a função ventricular. A LDE é uma nanopartícula lipídica, com estrutura semelhante à lipoproteína de baixa densidade (LDL). A LDE tem a capacidade de se concentrar em células com superexpressão de receptores de LDL, como em processos proliferativos e inflamatórios, sendo utilizada com um direcionador de fármacos a sítios específicos. Nosso laboratório demonstrou que o tratamento com metotrexato (MTX), um fármaco antiproliferativo e imunossupressor, associado à LDE reduziu acentuadamente as lesões ateroscleróticas na aorta de coelhos submetidos à dieta hipercolesterolêmica. Esses resultados nos levaram à hipótese de que a LDE-MTX possa ser utilizada para minimizar o processo inflamatório pós-IAM, determinante para o remodelamento cardíaco, e seus efeitos deletérios. O objetivo do trabalho foi investigar o efeito do tratamento da LDE-MTX sobre o remodelamento cardíaco em ratos submetidos ao IAM. Ratos machos Wistar (300-400g) foram submetidos ao modelo cirúrgico de IAM ou à cirurgia fictícia (SHAM). Os grupos foram divididos entre: SHAM (solução fisiológica), IAM-LDE, IAMMTXc (metotrexato comercial), IAM-LDE-MTX. Os animais foram tratados uma vez por semana na dose de 1 mg/kg intraperitonealmente, por 6 semanas. Após 24 horas do IAM e ao final do seguimento, foi realizado o ecocardiograma. O coração, o pulmão, o fígado e os rins foram coletados para obtenção do peso relativo dos órgãos. O tamanho do IAM foi estimado pela média dos tamanhos dos IAM externo e interno. A avaliação da necrose dos miócitos, processo inflamatório, diâmetro dos miócitos e fibrose miocárdica nas regiões subendocárdica (SE) e intersticial (INT) foi realizada na região remota ao IAM. Marcadores de estresse oxidativo, inflamação, fibrose, angiogênese e os receptores de lipoproteínas foram quantificados por PCR em tempo real. O tratamento com LDE-MTX diminuiu a dilatação do VE, hipertrofia cardíaca, volumes sistólicos e diastólicos, espessura do septo interventricular e da parede posterior e massa do VE, comparado aos grupos IAM-LDE e IAM-MTXc. Além disso, houve uma melhora de aproximadamente 40% da função sistólica do VE em relação aos demais grupos IAM. O tratamento com LDE-MTX não alterou a função diastólica. O peso relativo do coração e do pulmão foi menor no grupo IAM-LDE-MTX quando comparado ao IAM-LDE. Na histomorfometria, houve diminuição no tamanho do infarto no grupo IAM-LDE-MTX quando comparado com IAMLDE. A necrose, infiltrado inflamatório e fração de volume do colágeno nas regiões INT e SE foram menores no IAM-LDE-MTX em relação aos grupos IAM-LDE e IAM-MTXc, assim como o diâmetro dos miócitos. A expressão gênica dos marcadores de estresse oxidativo e fibrose foi menor no grupo IAM-LDE-MTX quando comparado ao grupo IAM-MTXc. Com relação à inflamação, o grupo IAM-LDE-MTX apresentou menor expressão do gene para TNF-alfa quando comparado aos grupos IAM-MTXc e SHAM. No que se refere ao receptor de lipoproteína, nos grupos IAM-LDE-MTX houve menor expressão do gene para receptor de lipoproteína de baixa densidade (LDLR) quando comparado ao grupo tratado com MTXc. Não foi observada toxicidade em nenhum grupo. Os resultados deste estudo indicam que o tratamento com LDE-MTX melhora significantemente a função cardíaca e atenua o remodelamento cardíaco em modelo experimental cirúrgico para IAM / Acute myocardial infarction (AMI) is the main cause of worldwide mortality. AMI is accompanied by cardiac remodeling, characterized by genetic, molecular and cellular alterations, with consequent changes in the size, shape and function of the heart, resulting in ventricular dysfunction and heart failure. Experimental and clinical evidence indicate that prevention or treatment of cardiac remodeling benefits the ventricular function. LDE is a lipid nanoparticle with a structure similar to low density lipoprotein (LDL). LDE has the ability to concentrate in cells with overexpression of LDL receptors, such as in proliferative and inflammatory processes, and is used with a drugtargeting agent at specific sites. Our laboratory demonstrated that the treatment with methotrexate (MTX), an antiproliferative and immunosuppressive drug, associated to LDE markedly reduced atherosclerotic lesions in aorta of rabbits submitted to the hypercholesterolemic diet. These results led us to the hypothesis that LDEMTX could be used to minimize the post-AMI inflammatory process, determinant for cardiac remodeling, and their deleterious effects. The aim of this study was to investigate the effect of LDE-MTX treatment on cardiac remodeling in rats submitted to AMI. Male Wistar rats (300-400g) were submitted to the surgical model of AMI or Sham surgery. The groups were divided into: SHAM (saline solution), AMI-LDE, AMI-MTXc (commercial methotrexate), AMI-LDE-MTX. The animals were treated once a week at a dose of 1 mg/kg intraperitoneally, for 6 weeks. After 24 hours of AMI and at the end of the follow-up, the echocardiogram was performed. The heart, lung, liver and kidneys were collected to obtain the relative weight of the organs. Infaction size was estimated by mean extern and intern size of IAM. Evaluation of myocyte necrosis, inflammatory process, myocyte diameter and myocardial fibrosis in the subendocardial (SE) and interstitial (INT) areas was performed in remote area from AMI. Markers of oxidative stress, inflammation, fibrosis, angiogenesis and lipoprotein receptors were quantified by quantitative real-time PCR. Treatment with LDE-MTX decreased LV dilation, cardiac hypertrophy, systolic and diastolic volumes, interventricular septum and posterior wall thickness and LV mass, compared to AMI-LDE and AMI-MTXc groups. In addition, there was an improvement of approximately 40% of LV systolic function compared to other AMI groups. Treatment with LDE-MTX did not alter diastolic function. The relative weight of the heart and lung were lower in the AMI-LDE-MTX group when compared to the AMI-LDE. In morphometry, infarct size decreased in the AMI-LDE-MTX group when compared to AMI-LDE. Necrosis, inflammatory infiltrate and collagen volume fraction in the INT and SE regions were lower in AMI-LDEMTX than in AMI-LDE and AMI-MTXc groups, as well as the myocyte diameter. The gene expression of oxidative stress and fibrosis markers were lower in the AMI-LDE-MTX group when compared to the AMI-MTXc. Regarding inflammation, the AMI-LDE-MTX group had lower expression of the TNF-alfa gene when compared to the AMI-MTXc group and the SHAM group. As regards the lipoprotein receptor, in the AMI-LDE-MTX there was lower expression of the gene for low-density lipoprotein (LDLR) receptor compared to MTXc treated animals. No toxicity was observed in any groups. The results of this study indicate that treatment with LDE-MTX significantly improves cardiac function and attenuates cardiac remodeling in an experimental surgical model for AMI

Estudos recentes sobre disfunção ventricular demonstram o potencial terapêutico da modulação da matriz extracelular. Isso se dá pela influência que a referida matriz tem sobre a função sistólica e a diastólica do coração. Outros estudos demonstram a influência do digital sobre os sistemas neurohormonais desbalanceados no cenário de disfunção ventricular levantando uma questão acerca do potencial do digital como modulador da deposição do colágeno intersticial e perivascular miocárdico. Sabendo-se da importância prognóstica que a concentração do colágeno no referido cenário tem, a literatura apresenta uma lacuna de conhecimento. Objetivo: Avaliar o papel do digital no remodelamento miocárdico em um modelo experimental. Material e Métodos: 60 ratos Wistar foram separados em 3 grupos de 20. Um grupo controle (GC); outro grupo submetido ao modelo experimental de uninefrectomia, administração de água de beber com 1% de NaCl e de aldosterona subcutânea (GA); e outro grupo submetido ao mesmo modelo experimental, mas também recebendo digitoxina na ração de comer na dose de 100 g/Kg/dia (GAD). Resultados: A fração de volume de colágeno intersticial e perivascular mostrou-se maior no GA comparado aos outros dois grupos (GC e GAD). O índice de desempenho miocárdico mostrou diferença estatisticamente significativa entre o GA (0,49 ± 0,08) e o GC (0,32 ± 0,06) e o GAD (0,4 ± 0,13) (p=0,001). Os níveis séricos de BNP mostraram diferença estatisticamente significativa entre o GA (1,07 ± 0,32 ng/ml) e o GC (0,75 ± 0,19 ng/ml) e o GAD (0,84 ± 0,21 ng/ml) (p=0,01). Os níveis de metaloproteinases não diferiram entre os grupos. Houve uma correlação positiva entre uma maior fração de encurtamento e menores níveis séricos de BNP no GAD. Conclusões: Esses dados demonstram que a digitoxina teve efeito reduzindo a deposição de colágeno intersticial e perivascular e melhorando a função cardíaca avaliada pelo BNP e IDM nesse modelo experimental / Recent studies on myocardial dysfunction are highlighting the therapeutic potential of the myocardial extracellular matrix management. Its interesting to highlight the importance of the dynamics of the cardiac extracellular matrix, because even the systolic and diastolic functions are implicated on it. Other studies showed that digital compounds may regulates the neuroendocrin misbalance due to myocardial impairment and influencing these systems the digital compounds may regulates the interstitial collagen deposition. Objective: To evaluate the role of the digital on a myocardial fibrosis in an experimental model, examining if the digital is able to prevent the collagen deposition. Methods: The sample was divided in 20 rats from the control group (CG); 20 rats submitted to a fibrosis experimental model in which the rats are uninefrectomized, drink water with 1% NaCl during the protocol and receive aldosterone through an osmotic minipump (AG); and 20 rats submitted to the same experimental model treated with digitoxin in a daily dose of 100 g/Kg (DAG). Results: The interstitial and perivascular collagen volume fraction showed a significant difference between the AG and the other 2 groups (CG and DAG). The myocardial performance index showed a significant difference between the AG (0.49 ± 0.08) and the CG (0.32 ± 0.06) and the DAG (0.40 ± 0.13) (p=0.001). The BNP levels showed a significant difference between the AG (1.07 ± 0.32 ng/ml) and the CG (0.75 ± 0.19 ng/ml) and the DAG (0.84 ± 0.21 ng/ml) (p=0.01). The metalloproteinases levels did not differ among the groups and there was a positive correlation between the shortening fraction and the BNP levels among the GAD animals. Conclusion: These data demonstrate the digitoxin positive effect on the myocardial collagen deposition in this experimental model of interstitial fibrosis and could have a new therapeutic target previously unexplored

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13259号 / 論医博第2177号 / 新制||医||1037(附属図書館) / (主査)教授 横出 正之, 教授 富樫 かおり, 教授 湊谷 謙司 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM