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1.
Intensive Care Med Exp ; 10(1): 38, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36117237

RESUMO

BACKGROUND: Timely identification of deteriorating COVID-19 patients is needed to guide changes in clinical management and admission to intensive care units (ICUs). There is significant concern that widely used Early warning scores (EWSs) underestimate illness severity in COVID-19 patients and therefore, we developed an early warning model specifically for COVID-19 patients. METHODS: We retrospectively collected electronic medical record data to extract predictors and used these to fit a random forest model. To simulate the situation in which the model would have been developed after the first and implemented during the second COVID-19 'wave' in the Netherlands, we performed a temporal validation by splitting all included patients into groups admitted before and after August 1, 2020. Furthermore, we propose a method for dynamic model updating to retain model performance over time. We evaluated model discrimination and calibration, performed a decision curve analysis, and quantified the importance of predictors using SHapley Additive exPlanations values. RESULTS: We included 3514 COVID-19 patient admissions from six Dutch hospitals between February 2020 and May 2021, and included a total of 18 predictors for model fitting. The model showed a higher discriminative performance in terms of partial area under the receiver operating characteristic curve (0.82 [0.80-0.84]) compared to the National early warning score (0.72 [0.69-0.74]) and the Modified early warning score (0.67 [0.65-0.69]), a greater net benefit over a range of clinically relevant model thresholds, and relatively good calibration (intercept = 0.03 [- 0.09 to 0.14], slope = 0.79 [0.73-0.86]). CONCLUSIONS: This study shows the potential benefit of moving from early warning models for the general inpatient population to models for specific patient groups. Further (independent) validation of the model is needed.

4.
Basic Res Cardiol ; 112(4): 42, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28540528

RESUMO

Optimal healing after myocardial infarction requires not only the induction of inflammation, but also its timely resolution. In patients, 30 days post myocardial infarction, circulating monocytes have increased expression of Semaphorin3A (Sema3A) as compared to directly after admission. This increased expression coincides with increased expression of Cx3CR1-a marker of non-classical monocytes that are important for immune resolution hence proper wound healing. In mice, the expression of Sema3A also increases in response to myocardial ischemia being expressed by infiltrating leukocytes. Comparing Sema3A heterozygote (HZ) and wild type (WT) mice post myocardial infarction, revealed increased presence of leukocytes in the cardiac tissues of HZ mice as compared to WT, with no differences in capillary density, collagen deposition, cardiomyocyte surface area, chemokine-or adhesion molecules expression. Whilst infarct sizes were similar 14 days after myocardial infarction in both genotypes, Sema3A HZ mice had thinner infarcts and reduced cardiac function as compared to their WT littermates. In vitro experiments were conducted to study the role of Sema3A in inflammation and resolution of inflammation as a potential explanation for the differences in leukocyte recruitment and cardiac function observed in our in vivo experiments. Here, recombinant Sema3A protein was able to affect the pro-inflammatory state of cultured bone marrow derived macrophages. First, the pro-inflammatory state was altered by the induced apoptosis of classical macrophages in the presence of Sema3A. Second, Sema3A promoted the polarization of classical macrophages to resolution-phase macrophages and enhanced their efferocytotic ability, findings that were reflected in the infarcted cardiac tissue of the Sema3A HZ mice. Finally, we demonstrated that besides promoting resolution of inflammation, Sema3A was also able to retard the migration of monocytes to the myocardium. Collectively our data demonstrate that Sema3A reduces cardiac inflammation and improves cardiac function after myocardial infarction by promoting the resolution of inflammation.


Assuntos
Infarto do Miocárdio/metabolismo , Miocardite/metabolismo , Miocárdio/metabolismo , Semaforina-3A/metabolismo , Cicatrização , Animais , Apoptose , Células Cultivadas , Quimiotaxia de Leucócito , Modelos Animais de Doenças , Feminino , Heterozigoto , Ativação de Macrófagos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Knockout , Monócitos/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocardite/genética , Miocardite/patologia , Miocardite/fisiopatologia , Miocárdio/patologia , Fenótipo , Recuperação de Função Fisiológica , Semaforina-3A/deficiência , Semaforina-3A/genética , Transdução de Sinais , Fatores de Tempo
6.
Aging Cell ; 10(5): 769-79, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21501375

RESUMO

To understand the process of cardiac aging, it is of crucial importance to gain insight into the age-related changes in gene expression in the senescent failing heart. Age-related cardiac remodeling is known to be accompanied by changes in extracellular matrix (ECM) gene and protein levels. Small noncoding microRNAs regulate gene expression in cardiac development and disease and have been implicated in the aging process and in the regulation of ECM proteins. However, their role in age-related cardiac remodeling and heart failure is unknown. In this study, we investigated the aging-associated microRNA cluster 17-92, which targets the ECM proteins connective tissue growth factor (CTGF) and thrombospondin-1 (TSP-1). We employed aged mice with a failure-resistant (C57Bl6) and failure-prone (C57Bl6 × 129Sv) genetic background and extrapolated our findings to human age-associated heart failure. In aging-associated heart failure, we linked an aging-induced increase in the ECM proteins CTGF and TSP-1 to a decreased expression of their targeting microRNAs 18a, 19a, and 19b, all members of the miR-17-92 cluster. Failure-resistant mice showed an opposite expression pattern for both the ECM proteins and the microRNAs. We showed that these expression changes are specific for cardiomyocytes and are absent in cardiac fibroblasts. In cardiomyocytes, modulation of miR-18/19 changes the levels of ECM proteins CTGF and TSP-1 and collagens type 1 and 3. Together, our data support a role for cardiomyocyte-derived miR-18/19 during cardiac aging, in the fine-tuning of cardiac ECM protein levels. During aging, decreased miR-18/19 and increased CTGF and TSP-1 levels identify the failure-prone heart.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/metabolismo , Insuficiência Cardíaca/patologia , MicroRNAs/metabolismo , Trombospondina 1/metabolismo , Adulto , Idoso , Envelhecimento/genética , Envelhecimento/fisiologia , Animais , Biópsia , Colágeno/metabolismo , Fator de Crescimento do Tecido Conjuntivo/genética , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Fibrose/genética , Fibrose/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Coração/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Pessoa de Meia-Idade , Família Multigênica , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Ratos , Ratos Endogâmicos Lew , Trombospondina 1/genética
7.
J Nucl Cardiol ; 17(6): 1065-72, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20658273

RESUMO

INTRODUCTION: The clinical feasibility of noninvasive imaging of interstitial alterations after myocardial infarction (MI) was assessed using a technetium-99m-labeled RGD imaging peptide (RIP). In experimental studies, RIP has been shown to target integrins associated with collagen-producing myofibroblasts (MFB). METHODS AND RESULTS: Ten patients underwent myocardial perfusion imaging (MPI) within the first week after MI. At 3 and 8 weeks after MI, RIP was administered intravenously and SPECT images acquired for interstitial imaging. RIP imaging was compared to initial MPI and to the extent of scar formation defined by late gadolinium-enhanced (LGE) cardiac magnetic resonance (CMR) imaging 1 year after MI. RIP uptake was observed in 7 of the 10 patients at both 3 and 8 weeks. Although, RIP uptake corresponded to areas of perfusion defects, it usually extended beyond the infarct zone to a variable extent; 2 of 7 patients showed tracer uptake throughout myocardium. In all positive cases, RIP uptake was similar to the extent of scar observed at 1 year by LGE-CMR imaging. CONCLUSION: This study demonstrates that RGD-based imaging early after MI may predict the eventual extent of scar formation, which often exceeds initial MPI deficit but colocalizes with LGE in CMR imaging performed subsequently.


Assuntos
Meios de Contraste/farmacologia , Imageamento por Ressonância Magnética/métodos , Infarto do Miocárdio/diagnóstico , Adulto , Idoso , Angiografia Coronária/métodos , Feminino , Gadolínio/farmacologia , Insuficiência Cardíaca , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Perfusão , Estudos Prospectivos , Tecnécio Tc 99m Sestamibi , Fatores de Tempo , Tomografia Computadorizada de Emissão de Fóton Único/métodos
8.
Arterioscler Thromb Vasc Biol ; 30(6): 1269-75, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20299689

RESUMO

OBJECTIVE: This study explored the relationship between coronary atherosclerotic plaque burden and quantifiable circulating levels of troponin measured with a recently introduced high sensitive cardiac troponin T (hs-cTnT) assay. METHODS AND RESULTS: Cardiac patients suspected of having coronary artery disease (CAD) but without acute coronary syndrome were studied. Cardiac troponin T levels were assessed using the fifth-generation hs-cTnT assay. All patients (n=615) underwent cardiac computed tomographic angiography (CCTA). On the basis of CCTA, patients were classified as having no CAD or mild (<50% lesion), moderate (50% to 70% lesion), severe (>70% lesion), or multivessel CAD (multiple >70% lesions). As a comparison, high-sensitivity C-reactive protein levels were measured. Progressively increasing hs-cTnT levels were found in patients with mild (median, 4.5 ng/L), moderate (median, 5.5 ng/L), severe (median, 5.7 ng/L), and multivessel (median, 8.6 ng/L) CAD compared with patients without CAD (median, 3.7 ng/L) (all P<0.01). For high-sensitivity C-reactive protein and N-terminal pro-B-type natriuretic peptide, no such relationship was observed. In patients without CAD, 11% showed hs-cTnT levels in the highest quartile, compared with 62% in the multivessel disease group (P<0.05). Multivariance analysis identified hs-cTnT as an independent risk factor for the presence of CAD. CONCLUSIONS: In patients without acute coronary syndrome, even mild CAD is associated with quantifiable circulating levels of hs-cTnT.


Assuntos
Estenose Coronária/sangue , Troponina T/sangue , Adulto , Idoso , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Distribuição de Qui-Quadrado , Angiografia Coronária/métodos , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/etiologia , Feminino , Humanos , Funções Verossimilhança , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Razão de Chances , Fragmentos de Peptídeos/sangue , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Regulação para Cima
9.
Hypertension ; 55(2): 249-56, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20048198

RESUMO

Syndecan-1 (Synd1) is a transmembrane heparan sulfate proteoglycan that functions as a coreceptor for various growth factors and modulates signal transduction. The present study investigated whether Synd1, by affecting growth factor signaling, may play a role in hypertension-induced cardiac fibrosis and dysfunction. Expression of Synd1 was increased significantly in mouse hearts with angiotensin II-induced hypertension, which was spatially related to cardiac fibrosis. Angiotensin II significantly impaired fractional shortening and induced cardiac fibrosis in wild-type mice, whereas these effects were blunted in Synd1-null mice. Angiotensin II significantly increased cardiac expression of connective tissue growth factor and collagen type I and III in wild-type mice, which was blunted in Synd1-null mice. These findings were confirmed in vitro, where angiotensin II induced the expression of both connective tissue growth factor and collagen I in fibroblasts. The absence of Synd1 in either Synd1-null fibroblasts, after knockdown of Synd1 by short hairpin RNA, or after inhibition of heparan sulfates by protamine attenuated this increase, which was associated with reduced phosphorylation of Smad2. In conclusion, loss of Synd1 reduces cardiac fibrosis and dysfunction during angiotensin II-induced hypertension.


Assuntos
Angiotensina II/farmacologia , Miocárdio/patologia , Proteína Smad2/metabolismo , Sindecana-1/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Fibrose/patologia , Regulação da Expressão Gênica , Hipertensão/induzido quimicamente , Hipertensão/complicações , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Probabilidade , RNA Mensageiro/análise , Distribuição Aleatória , Proteína Smad2/efeitos dos fármacos , Proteína Smad2/genética , Sindecana-1/genética
10.
J Cell Commun Signal ; 3(3-4): 201-13, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19798592

RESUMO

Cardiac remodeling after myocardial injury involves inflammation, angiogenesis, left ventricular hypertrophy and matrix remodeling. Thrombospondins (TSPs) belong to the group of matricellular proteins, which are non-structural extracellular matrix proteins that modulate cell-matrix interactions and cell function in injured tissues or tumors. They interact with different matrix and membrane-bound proteins due to their diverse functional domains. That the expression of TSPs strongly increases during cardiac stress or injury indicates an important role for them during cardiac remodeling. Recently, the protective properties of TSP expression against heart failure have been acknowledged. The current review will focus on the biological role of TSPs in the ischemic and hypertensive heart, and will describe the functional consequences of TSP polymorphisms in cardiac disease.

11.
Circulation ; 120(16): 1585-97, 2009 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-19805649

RESUMO

BACKGROUND: The progressive shift from a young to an aged heart is characterized by alterations in the cardiac matrix. The present study investigated whether the matricellular protein thrombospondin-2 (TSP-2) may affect cardiac dimensions and function with physiological aging of the heart. METHODS AND RESULTS: TSP-2 knockout (KO) and wild-type mice were followed up to an age of 60 weeks. Survival rate, cardiac function, and morphology did not differ at a young age in TSP-2 KO compared with wild-type mice. However, >55% of the TSP-2 KO mice died between 24 and 60 weeks of age, whereas <10% of the wild-type mice died. In the absence of TSP-2, older mice displayed a severe dilated cardiomyopathy with impaired systolic function, increased cardiac dilatation, and fibrosis. Ultrastructural analysis revealed progressive myocyte stress and death, accompanied by an inflammatory response and replacement fibrosis, in aging TSP-2 KO animals, whereas capillary or coronary morphology or density was not affected. Importantly, adeno-associated virus-9 gene-mediated transfer of TSP-2 in 7-week-old TSP-2 KO mice normalized their survival and prevented dilated cardiomyopathy. In TSP-2 KO animals, age-related cardiomyopathy was accompanied by increased matrix metalloproteinase-2 and decreased tissue transglutaminase-2 activity, together with impaired collagen cross-linking. At the cardiomyocyte level, TSP-2 deficiency in vivo and its knockdown in vitro decreased the activation of the Akt survival pathway in cardiomyocytes. CONCLUSIONS: TSP-2 expression in the heart protects against age-dependent dilated cardiomyopathy.


Assuntos
Envelhecimento , Cardiomiopatia Dilatada/etiologia , Miocárdio/metabolismo , Trombospondinas/deficiência , Animais , Cardiomiopatia Dilatada/mortalidade , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/prevenção & controle , Morte Celular , Ativação Enzimática , Feminino , Fibrose , Técnicas de Transferência de Genes , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Miocardite/etiologia , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/ultraestrutura , Proteínas Proto-Oncogênicas c-akt/metabolismo , Trombospondinas/genética , Regulação para Cima
12.
Circ Res ; 104(2): 170-8, 6p following 178, 2009 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-19096030

RESUMO

The myocardium of the failing heart undergoes a number of structural alterations, most notably hypertrophy of cardiac myocytes and an increase in extracellular matrix proteins, often seen as primary fibrosis. Connective tissue growth factor (CTGF) is a key molecule in the process of fibrosis and therefore seems an attractive therapeutic target. Regulation of CTGF expression at the promoter level has been studied extensively, but it is unknown how CTGF transcripts are regulated at the posttranscriptional level. Here we provide several lines of evidence to show that CTGF is importantly regulated by 2 major cardiac microRNAs (miRNAs), miR-133 and miR-30. First, the expression of both miRNAs was inversely related to the amount of CTGF in 2 rodent models of heart disease and in human pathological left ventricular hypertrophy. Second, in cultured cardiomyocytes and fibroblasts, knockdown of these miRNAs increased CTGF levels. Third, overexpression of miR-133 or miR-30c decreased CTGF levels, which was accompanied by decreased production of collagens. Fourth, we show that CTGF is a direct target of these miRNAs, because they directly interact with the 3' untranslated region of CTGF. Taken together, our results indicate that miR-133 and miR-30 importantly limit the production of CTGF. We also provide evidence that the decrease of these 2 miRNAs in pathological left ventricular hypertrophy allows CTGF levels to increase, which contributes to collagen synthesis. In conclusion, our results show that both miR-133 and miR-30 directly downregulate CTGF, a key profibrotic protein, and thereby establish an important role for these miRNAs in the control of structural changes in the extracellular matrix of the myocardium.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/metabolismo , Matriz Extracelular/metabolismo , Insuficiência Cardíaca/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , MicroRNAs/metabolismo , Miocárdio/metabolismo , Processamento Pós-Transcricional do RNA , Remodelação Ventricular , Regiões 3' não Traduzidas , Animais , Animais Recém-Nascidos , Sequência de Bases , Células Cultivadas , Biologia Computacional , Fator de Crescimento do Tecido Conjuntivo/genética , Modelos Animais de Doenças , Feminino , Fibrose , Técnicas de Silenciamento de Genes , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Miocárdio/patologia , Filogenia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Renina/genética , Renina/metabolismo , Regulação para Cima , Remodelação Ventricular/genética
13.
J Exp Med ; 206(1): 113-23, 2009 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-19103879

RESUMO

The matricellular protein SPARC (secreted protein, acidic and rich in cysteine, also known as osteonectin) mediates cell-matrix interactions during wound healing and regulates the production and/or assembly of the extracellular matrix (ECM). This study investigated whether SPARC functions in infarct healing and ECM maturation after myocardial infarction (MI). In comparison with wild-type (WT) mice, animals with a targeted inactivation of SPARC exhibited a fourfold increase in mortality that resulted from an increased incidence of cardiac rupture and failure after MI. SPARC-null infarcts had a disorganized granulation tissue and immature collagenous ECM. In contrast, adenoviral overexpression of SPARC in WT mice improved the collagen maturation and prevented cardiac dilatation and dysfunction after MI. In cardiac fibroblasts in vitro, reduction of SPARC by short hairpin RNA attenuated transforming growth factor beta (TGF)-mediated increase of Smad2 phosphorylation, whereas addition of recombinant SPARC increased Smad2 phosphorylation concordant with increased Smad2 phosphorylation in SPARC-treated mice. Importantly, infusion of TGF-beta rescued cardiac rupture in SPARC-null mice but did not significantly alter infarct healing in WT mice. These findings indicate that local production of SPARC is essential for maintenance of the integrity of cardiac ECM after MI. The protective effects of SPARC emphasize the potential therapeutic applications of this protein to prevent cardiac dilatation and dysfunction after MI.


Assuntos
Ruptura Cardíaca Pós-Infarto/metabolismo , Infarto do Miocárdio/metabolismo , Osteonectina/deficiência , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas da Matriz Extracelular/genética , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Tecido de Granulação/efeitos dos fármacos , Tecido de Granulação/metabolismo , Tecido de Granulação/patologia , Coração/fisiopatologia , Ruptura Cardíaca Pós-Infarto/fisiopatologia , Ruptura Cardíaca Pós-Infarto/prevenção & controle , Hemodinâmica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Osteonectina/genética , Osteonectina/fisiologia , Ratos , Ratos Endogâmicos Lew , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/genética , Análise de Sobrevida , Fator de Crescimento Transformador beta/farmacologia , Fator de Crescimento Transformador beta/fisiologia , Fator de Crescimento Transformador beta/uso terapêutico
14.
J Exp Med ; 204(5): 1227-35, 2007 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-17485520

RESUMO

The intercalated disc (ID) of cardiac myocytes is emerging as a crucial structure in the heart. Loss of ID proteins like N-cadherin causes lethal cardiac abnormalities, and mutations in ID proteins cause human cardiomyopathy. A comprehensive screen for novel mechanisms in failing hearts demonstrated that expression of the lysosomal integral membrane protein 2 (LIMP-2) is increased in cardiac hypertrophy and heart failure in both rat and human myocardium. Complete loss of LIMP-2 in genetically engineered mice did not affect cardiac development; however, these LIMP-2 null mice failed to mount a hypertrophic response to increased blood pressure but developed cardiomyopathy. Disturbed cadherin localization in these hearts suggested that LIMP-2 has important functions outside lysosomes. Indeed, we also find LIMP-2 in the ID, where it associates with cadherin. RNAi-mediated knockdown of LIMP-2 decreases the binding of phosphorylated beta-catenin to cadherin, whereas overexpression of LIMP-2 has the opposite effect. Collectively, our data show that LIMP-2 is crucial to mount the adaptive hypertrophic response to cardiac loading. We demonstrate a novel role for LIMP-2 as an important mediator of the ID.


Assuntos
Antígenos CD36/metabolismo , Cardiomiopatia Dilatada/metabolismo , Hipertensão/complicações , Proteínas de Membrana Lisossomal/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Estenose da Valva Aórtica/metabolismo , Antígenos CD36/genética , Caderinas/metabolismo , Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/genética , Primers do DNA , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/fisiologia , Humanos , Proteínas de Membrana Lisossomal/genética , Camundongos , Camundongos Knockout , Miócitos Cardíacos/patologia , Interferência de RNA , Ratos , Ratos Sprague-Dawley , beta Catenina/metabolismo
15.
Am J Physiol Renal Physiol ; 293(1): F428-37, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17429032

RESUMO

Regulation of protein kinase activities is crucial in both physiology and disease, but analysis is hampered by the multitude and complexity of kinase networks. We used novel peptide array chips containing 1,152 known kinase substrate sequences to profile different kinase activities in renal lysates from homozygous Ren2 rats, a model characterized by hypertension and angiotensin II (ANG II)-mediated renal fibrosis, compared with Sprague-Dawley (SD) control rats and Ren2 rats treated with an angiotensin-converting enzyme inhibitor (ACEi). Five-wk-old homozygous Ren2 rats were left untreated or treated with the ACEi ramipril (1 mg.kg(-1).day(-1)) for 4 wk; age-matched SD rats served as controls (n = 5 each). Peptide array chips were incubated with renal cortical lysates in the presence of radioactively labeled ATP. Radioactivity incorporated into the substrate motifs was measured to quantify kinase activity. A number of kinases with modulated activities, which might contribute to renal damage, were validated by Western blotting, immunoprecipitation, and immunohistochemistry. Relevant kinases identified by the peptide array and confirmed using conventional techniques included p38 MAP kinase and PDGF receptor-beta, which were increased in Ren2 and reversed by ACEi. Furthermore, insulin receptor signaling was reduced in Ren2 compared with control rats, and G protein-coupled receptor kinase (GRK) activity decreased in Ren2 + ACEi compared with untreated Ren2 rats. Array-based profiling of tissue kinase activities in ANG II-mediated renal damage provides a powerful tool for identification of relevant kinase pathways in vivo and may lead to novel strategies for therapy.


Assuntos
Angiotensina II/fisiologia , Hipertensão Renal/patologia , Rim/metabolismo , Rim/patologia , Proteínas Quinases/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Pressão Sanguínea/fisiologia , Western Blotting , Receptores ErbB/metabolismo , Regulação Enzimológica da Expressão Gênica/fisiologia , Genoma , Hipertensão Renal/enzimologia , Imuno-Histoquímica , Imunoprecipitação , Masculino , Fosforilação , Ratos , Receptor de Insulina/fisiologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Circulation ; 115(4): 475-82, 2007 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-17242279

RESUMO

BACKGROUND: The cell-associated proteoglycan syndecan-1 (Synd1) closely regulates inflammation and cell-matrix interactions during wound healing and tumorigenesis. The present study investigated whether Synd1 may also regulate cardiac inflammation, matrix remodeling, and function after myocardial infarction (MI). METHODS AND RESULTS: First, we showed increased protein and mRNA expression of Synd1 from 24 hours on, reaching its maximum at 7 days after MI and declining thereafter. Targeted deletion of Synd1 resulted in increased inflammation and accelerated, yet functionally adverse, infarct healing after MI. In concordance, adenoviral gene expression of Synd1 protected against exaggerated inflammation after MI, mainly by reducing transendothelial adhesion and migration of leukocytes, as shown in vitro. Increased inflammation in the absence of Synd1 resulted in increased monocyte chemoattractant protein-1 expression, increased activity of matrix metalloproteinase-2 and -9, and decreased activity of tissue transglutaminase, associated with increased collagen fragmentation and disorganization. Exaggerated inflammation and adverse matrix remodeling in the absence of Synd1 increased cardiac dilatation and impaired systolic function, whereas gene overexpression of Synd1 reduced inflammation and protected against cardiac dilatation and failure. CONCLUSIONS: Increased expression of Synd1 in the infarct protects against exaggerated inflammation and adverse infarct healing, thereby reducing cardiac dilatation and dysfunction after MI in mice.


Assuntos
Cardiomiopatia Dilatada/genética , Infarto do Miocárdio/genética , Sindecana-1/genética , Sindecana-1/fisiologia , Remodelação Ventricular/genética , Animais , Cardiomiopatia Dilatada/imunologia , Cardiomiopatia Dilatada/fisiopatologia , Colágeno/genética , Citocinas/genética , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Coração/fisiologia , Leucócitos/imunologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Mutagênese , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/enzimologia , Miocárdio/patologia , RNA Mensageiro/metabolismo , Sístole/genética , Remodelação Ventricular/imunologia
18.
Hypertension ; 47(3): 467-74, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16432052

RESUMO

Imatinib specifically inhibits receptor tyrosine kinase signaling and is clinically used to treat leukemia. Receptor tyrosine kinases not only mediate tumor growth but also initiate adverse signaling in heart failure. We investigated whether imatinib, by inhibiting the platelet-derived growth factor receptor-beta (PDGFRbeta), prevents cardiac and renal damage in TGR(mRen2)27 (Ren2) rats. Eight-week-old male homozygous Ren2 and Sprague Dawley rats were treated either with imatinib (30 mg/kg; STI-571) or placebo for 8 weeks (Ren2 n=12 for each group; Sprague Dawley n=6 for each group). Imatinib did not affect blood pressure or left ventricular (LV) hypertrophy in both groups. Imatinib attenuated the decline in fractional shortening (imatinib versus Ren2 placebo 45+/-4.5% versus 32+/-3%; n=7-11; P<0.05) and in diastolic function in Ren2 rats (baseline diastolic dP/dt corrected for systolic blood pressure Ren2 imatinib versus Ren2 placebo 38.6+/-0.67 versus 35.3+/-0.41 [1 . s(-1)]; n=7-11; P<0.05). This was associated with decreased cardiac fibrosis and decreased activation of PDGFRbeta and extracellular signal-regulated kinase 1/2. Renal microvascular hypertrophy and perivascular fibrosis in Ren2 rats were significantly decreased by imatinib. In vitro, imatinib blocked angiotensin II-induced activation of the PDGFRbeta and significantly decreased fibroblast proliferation and collagen production. In conclusion, imatinib did not affect LV hypertrophy but attenuated the decline in cardiac function and reduced renal microvascular damage associated with reduced activation of the PDGFRbeta. The simultaneous improvement in both heart and kidneys suggests that inhibition of the PDGFRbeta has broad protective effects that may provide novel avenues for a blood pressure-independent protection against end-organ damage.


Assuntos
Cardiopatias/prevenção & controle , Homozigoto , Hipertensão/genética , Nefropatias/prevenção & controle , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Renina/genética , Animais , Animais Geneticamente Modificados , Arteríolas/efeitos dos fármacos , Arteríolas/patologia , Benzamidas , Pressão Sanguínea/efeitos dos fármacos , Células Cultivadas , Fibrose , Hemodinâmica/efeitos dos fármacos , Hipertensão/complicações , Mesilato de Imatinib , Rim/irrigação sanguínea , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Masculino , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Receptores Proteína Tirosina Quinases/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos
19.
Cardiovasc Res ; 69(3): 604-13, 2006 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16360129

RESUMO

The post-myocardial infarction wound repair process involves temporarily overlapping phases that include inflammation, formation of granulation tissue, scar formation, and overall left ventricle (LV) remodelling. The myocardial extracellular matrix (ECM) plays an important role in maintaining the structural and functional integrity of the heart and is centrally involved in wound repair post-myocardial infarction (MI). The main proteolytic system involved in the degradation of the ECM in the heart is the matrix metalloproteinase (MMPs) system. The present review will focus on the importance of the unique temporal and spatial window of MMPs and their inhibitors (TIMPs) within the different wound healing phases post-MI. It summarizes (1) the MMP/TIMP levels at different time points post-MI, (2) the alterations seen in post-MI healing in genetically modified mice, and (3) the effects and limitations of therapeutic MMP-inhibition post-MI.


Assuntos
Matriz Extracelular/enzimologia , Metaloproteinases da Matriz/metabolismo , Infarto do Miocárdio/enzimologia , Inibidores Teciduais de Metaloproteinases/metabolismo , Animais , Inibidores de Metaloproteinases de Matriz , Camundongos , Camundongos Transgênicos , Fatores de Tempo , Remodelação Ventricular
20.
Cardiovasc Res ; 64(1): 24-31, 2004 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-15364610

RESUMO

Matricellular proteins are extracellular matrix proteins that modulate cell-matrix interactions and cell function, and do not seem to have a direct structural role. The family includes tenascin-C (TN-C), tenascin-X (TN-X), osteonectin, osteopontin, thrombospondin-1 (TSP1) and thrombospondin-2 (TSP2). Expression of matricellular proteins is high during embryogenesis, but almost absent during normal postnatal life. Interestingly, it re-appears in response to injury. Left ventricular remodeling is a complicated process that occurs in the stressed heart, and is still not completely understood. Several members of the matricellular protein family, like tenascin-C, osteopontin, and osteonectin are up-regulated after cardiac injury. Therefore, this group of proteins may have crucial functions in the heart coping with stress. This review will focus on the expression, regulation and function of these matricellular proteins, and will discuss the crucial functions that these proteins might exert during remodeling of the stressed heart.


Assuntos
Proteínas da Matriz Extracelular/fisiologia , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Remodelação Ventricular/fisiologia , Humanos
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