Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros












Base de dados
Intervalo de ano de publicação
1.
Cardiology ; 145(3): 187-198, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31968347

RESUMO

INTRODUCTION: The heart undergoes myocardial remodeling during progression to heart failure following pressure overload. Myocardial remodeling is associated with structural and functional changes in cardiac myocytes, fibroblasts, and the extracellular matrix (ECM) and is accompanied by inflammation. Cardiac fibrosis, the accumulation of ECM molecules including collagens and collagen cross-linking, contributes both to impaired systolic and diastolic function. Insufficient mechanistic insight into what regulates cardiac fibrosis during pathological conditions has hampered therapeutic so-lutions. Lumican (LUM) is an ECM-secreted proteoglycan known to regulate collagen fibrillogenesis. Its expression in the heart is increased in clinical and experimental heart failure. Furthermore, LUM is important for survival and cardiac remodeling following pressure overload. We have recently reported that total lack of LUM increased mortality and left ventricular dilatation, and reduced collagen expression and cross-linking in LUM knockout mice after aortic banding (AB). Here, we examined the effect of LUM on myocardial remodeling and function following pressure overload in a less extreme mouse model, where cardiac LUM level was reduced to 50% (i.e., moderate loss of LUM). METHODS AND RESULTS: mRNA and protein levels of LUM were reduced to 50% in heterozygous LUM (LUM+/-) hearts compared to wild-type (WT) controls. LUM+/- mice were subjected to AB. There was no difference in survival between LUM+/- and WT mice post-AB. Echocardiography revealed no striking differences in cardiac geometry between LUM+/- and WT mice 2, 4, and 6 weeks post-AB, although markers of diastolic dysfunction indicated better function in LUM+/- mice. LUM+/- hearts revealed reduced cardiac fibrosis assessed by histology. In accordance, the expression of collagen I and III, the main fibrillar collagens in the heart, and other ECM molecules central to fibrosis, i.e. including periostin and fibronectin, was reduced in the hearts of LUM+/- compared to WT 6 weeks post-AB. We found no differences in collagen cross-linking between LUM+/- and WT mice post-AB, as assessed by histology and qPCR. CONCLUSIONS: Moderate lack of LUM attenuated cardiac fibrosis and improved diastolic dysfunction following pressure overload in mice, adding to the growing body of evidence suggesting that LUM is a central profibrotic molecule in the heart that could serve as a potential therapeutic target.


Assuntos
Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Lumicana/fisiologia , Miofibroblastos/metabolismo , Animais , Colágeno/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Matriz Extracelular/metabolismo , Ventrículos do Coração/patologia , Lumicana/genética , Masculino , Camundongos , Camundongos Knockout , Miofibroblastos/patologia , Remodelação Ventricular
2.
Sci Rep ; 9(1): 9206, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235849

RESUMO

Left ventricular (LV) dilatation is a key step in transition to heart failure (HF) in response to pressure overload. Cardiac extracellular matrix (ECM) contains fibrillar collagens and proteoglycans, important for maintaining tissue integrity. Alterations in collagen production and cross-linking are associated with cardiac LV dilatation and HF. Lumican (LUM) is a collagen binding proteoglycan with increased expression in hearts of patients and mice with HF, however, its role in cardiac function remains poorly understood. To examine the role of LUM in pressure overload induced cardiac remodeling, we subjected LUM knock-out (LUMKO) mice to aortic banding (AB) and treated cultured cardiac fibroblasts (CFB) with LUM. LUMKO mice exhibited increased mortality 1-14 days post-AB. Echocardiography revealed increased LV dilatation, altered hypertrophic remodeling and exacerbated contractile dysfunction in surviving LUMKO 1-10w post-AB. LUMKO hearts showed reduced collagen expression and cross-linking post-AB. Transcriptional profiling of LUMKO hearts by RNA sequencing revealed 714 differentially expressed transcripts, with enrichment of cardiotoxicity, ECM and inflammatory pathways. CFB treated with LUM showed increased mRNAs for markers of myofibroblast differentiation, proliferation and expression of ECM molecules important for fibrosis, including collagens and collagen cross-linking enzyme lysyl oxidase. In conclusion, we report the novel finding that lack of LUM attenuates collagen cross-linking in the pressure-overloaded heart, leading to increased mortality, dilatation and contractile dysfunction in mice.


Assuntos
Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Lumicana/fisiologia , Miofibroblastos/metabolismo , Animais , Colágeno/metabolismo , Dilatação , Matriz Extracelular/metabolismo , Feminino , Células HEK293 , Ventrículos do Coração/patologia , Humanos , Camundongos , Miofibroblastos/patologia
3.
PLoS One ; 13(7): e0201422, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30052659

RESUMO

Pressure overload of the heart leads to cardiac remodeling that may progress into heart failure, a common, morbid and mortal condition. Increased mechanistic insight into remodeling is instrumental for development of novel heart failure treatment. Cardiac remodeling comprises cardiomyocyte hypertrophic growth, extracellular matrix alterations including fibrosis, and inflammation. Fibromodulin is a small leucine-rich proteoglycan that regulates collagen fibrillogenesis. Fibromodulin is expressed in the cardiac extracellular matrix, however its role in the heart remains largely unknown. We investigated fibromodulin levels in myocardial biopsies from heart failure patients and mice, subjected fibromodulin knock-out (FMOD-KO) mice to pressure overload by aortic banding, and overexpressed fibromodulin in cultured cardiomyocytes and cardiac fibroblasts using adenovirus. Fibromodulin was 3-10-fold upregulated in hearts of heart failure patients and mice. Both cardiomyocytes and cardiac fibroblasts expressed fibromodulin, and its expression was increased by pro-inflammatory stimuli. Without stress, FMOD-KO mice showed no cardiac phenotype. Upon aortic banding, left ventricles of FMOD-KO mice developed mildly exacerbated hypertrophic remodeling compared to wild-type mice, with increased cardiomyocyte size and altered infiltration of leukocytes. There were no differences in mortality, left ventricle dilatation, dysfunction or expression of heart failure markers. Although collagen amount and cross-linking were comparable in FMOD-KO and wild-type, overexpression of fibromodulin in cardiac fibroblasts in vitro decreased their migratory capacity and expression of fibrosis-associated molecules, i.e. the collagen-cross linking enzyme lysyl oxidase, transglutaminase 2 and periostin. In conclusion, despite a robust fibromodulin upregulation in clinical and experimental heart failure, FMOD-KO mice showed a relatively mild hypertrophic phenotype. In cultured cardiac fibroblasts, fibromodulin has anti-fibrotic effects.


Assuntos
Cardiomegalia/metabolismo , Matriz Extracelular/metabolismo , Fibromodulina/biossíntese , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Animais , Biomarcadores , Cardiomegalia/genética , Cardiomegalia/patologia , Modelos Animais de Doenças , Matriz Extracelular/genética , Matriz Extracelular/patologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibromodulina/genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia
4.
Cardiovasc Res ; 106(1): 32-42, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25694587

RESUMO

AIMS: In pressure overload, left ventricular (LV) dilatation is a key step in transition to heart failure (HF). We recently found that collagen VIII (colVIII), a non-fibrillar collagen and extracellular matrix constituent, was reduced in hearts of mice with HF and correlated to degree of dilatation. A reduction in colVIII might be involved in LV dilatation, and we here examined the role of reduced colVIII in pressure overload-induced remodelling using colVIII knock-out (col8KO) mice. METHODS AND RESULTS: Col8KO mice exhibited increased mortality 3-9 days after aortic banding (AB) and increased LV dilatation from day one after AB, compared with wild type (WT). LV dilatation remained increased over 56 days. Forty-eight hours after AB, LV expression of main structural collagens (I and III) was three-fold increased in WT mice, but these collagens were unaltered in the LV of col8KO mice together with reduced expression of the pro-fibrotic cytokine TGF-ß, SMAD2 signalling, and the myofibroblast markers Pxn, α-SMA, and SM22. Six weeks after AB, LV collagen mRNA expression and protein were increased in col8KO mice, although less pronounced than in WT. In vitro, neonatal cardiac fibroblasts from col8KO mice showed lower expression of TGF-ß, Pxn, α-SMA, and SM22 and reduced migratory ability possibly due to increased RhoA activity and reduced MMP2 expression. Stimulation with recombinant colVIIIα1 increased TGF-ß expression and fibroblast migration. CONCLUSION: Lack of colVIII reduces myofibroblast differentiation and fibrosis and promotes early mortality and LV dilatation in response to pressure overload in mice.


Assuntos
Colágeno Tipo VIII/deficiência , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Hipertrofia Ventricular Esquerda/mortalidade , Hipertrofia Ventricular Esquerda/fisiopatologia , Miocárdio/patologia , Animais , Pressão Arterial/fisiologia , Diferenciação Celular/fisiologia , Colágeno Tipo VIII/metabolismo , Modelos Animais de Doenças , Fibroblastos/patologia , Fibrose/prevenção & controle , Insuficiência Cardíaca/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Técnicas In Vitro , Masculino , Camundongos , Camundongos Knockout , Miocárdio/metabolismo , Transdução de Sinais/fisiologia , Taxa de Sobrevida , Fator de Crescimento Transformador beta/metabolismo , Proteínas rho de Ligação ao GTP/fisiologia , Proteína rhoA de Ligação ao GTP
5.
J Mol Cell Cardiol ; 76: 148-57, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25169971

RESUMO

Pressure overload-induced TGF-ß signaling activates cardiac fibroblasts (CFB) and leads to increased extracellular matrix (ECM) protein synthesis including fibrosis. Excessive ECM accumulation may in turn affect cardiac function contributing to development of heart failure. The aim of this study was to examine the effects of SM16, an orally active small molecular inhibitor of ALK5, on pressure overload-induced cardiac fibrosis. One week after aortic banding (AB), C57Bl/6J mice were randomized to standard chow or chow with SM16. Sham operated animals served as controls. Following 4 weeks AB, mice were characterized by echocardiography and cardiovascular magnetic resonance before sacrifice. SM16 abolished phosphorylation of SMAD2 induced by AB in vivo and by TGF-ß in CFB in vitro. Interestingly, Masson Trichrome and Picrosirius Red stained myocardial left ventricular tissue revealed reduced development of fibrosis and collagen cross-linking following AB in the SM16 treated group, which was confirmed by reduced hydroxyproline incorporation. Furthermore, treatment with SM16 attenuated mRNA expression following induction of AB in vivo and stimulation with TGF-ß in CFB in vitro of Col1a2, the cross-linking enzyme LOX, and the pro-fibrotic glycoproteins SPARC and osteopontin. Reduced ECM synthesis by CFB and a reduction in myocardial stiffness due to attenuated development of fibrosis and collagen cross-linking might have contributed to the improved diastolic function and cardiac output seen in vivo, in combination with reduced lung weight and ANP expression by treatment with SM16. Despite these beneficial effects on cardiac function and development of heart failure, mice treated with SM16 exhibited increased mortality, increased LV dilatation and inflammatory heart valve lesions that may limit the use of SM16 and possibly also other small molecular inhibitors of ALK5, as future therapeutic drugs.


Assuntos
Compostos Azabicíclicos/administração & dosagem , Cardiotônicos/administração & dosagem , Hipertrofia Ventricular Esquerda/metabolismo , Miocárdio/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Administração Oral , Animais , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/fisiopatologia , Células Cultivadas , Colágeno/metabolismo , Avaliação Pré-Clínica de Medicamentos , Matriz Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose , Células HEK293 , Humanos , Hipertrofia Ventricular Esquerda/fisiopatologia , Camundongos Endogâmicos C57BL , Cultura Primária de Células , Processamento de Proteína Pós-Traducional , Receptor do Fator de Crescimento Transformador beta Tipo I , Transdução de Sinais , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Pressão Ventricular
7.
FEBS J ; 280(10): 2382-98, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23480731

RESUMO

During progression to heart failure (HF), myocardial extracellular matrix (ECM) alterations and tissue inflammation are central. Lumican is an ECM-localized proteoglycan associated with inflammatory conditions and known to bind collagens. We hypothesized that lumican plays a role in the dynamic alterations in cardiac ECM during development of HF. Thus, we examined left ventricular cardiac lumican in a mouse model of pressure overload and in HF patients, and investigated expression, regulation and effects of increased lumican in cardiac fibroblasts. After 4 weeks of aortic banding, mice were divided into groups of hypertrophy (AB) and HF (ABHF) based on lung weight and left atrial diameter. Sham-operated mice were used as controls. Accordingly, cardiac lumican mRNA and protein levels were increased in mice with ABHF. Similarly, cardiac biopsies from patients with end-stage HF revealed increased lumican mRNA and protein levels compared with control hearts. In vitro, mechanical stretch and the proinflammatory cytokine interleukin-1ß increased lumican mRNA as well as secreted lumican protein from cardiac fibroblasts. Stimulation with recombinant glycosylated lumican increased collagen type I alpha 2, lysyl oxidase and transforming growth factor-ß1 mRNA, which was attenuated by costimulation with an inhibitor of the proinflammatory transcription factor NFκB. Furthermore, lumican increased the levels of the dimeric form of collagen type I, decreased the activity of the collagen-degrading enzyme matrix metalloproteinase-9 and increased the phosphorylation of fibrosis-inducing SMAD3. In conclusion, cardiac lumican is increased in experimental and clinical HF. Inflammation and mechanical stimuli induce lumican production by cardiac fibroblasts and increased lumican altered molecules important for cardiac remodeling and fibrosis in cardiac fibroblasts, indicating a role in HF development.


Assuntos
Proteoglicanas de Sulfatos de Condroitina/metabolismo , Fibroblastos/patologia , Insuficiência Cardíaca/patologia , Interleucina-1beta/farmacologia , Sulfato de Queratano/metabolismo , Adulto , Animais , Animais Recém-Nascidos , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Proteoglicanas de Sulfatos de Condroitina/genética , Proteoglicanas de Sulfatos de Condroitina/farmacologia , Colágeno Tipo I/metabolismo , Ecocardiografia , Matriz Extracelular/metabolismo , Feminino , Fibroblastos/metabolismo , Insuficiência Cardíaca/metabolismo , Humanos , Sulfato de Queratano/genética , Sulfato de Queratano/farmacologia , Lumicana , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Tamanho do Órgão , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Proteína Smad3/genética , Proteína Smad3/metabolismo , Estresse Mecânico , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
8.
J Appl Physiol (1985) ; 114(8): 988-97, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23412898

RESUMO

On the basis of the role of small, leucine-rich proteoglycans (SLRPs) in fibrogenesis and inflammation, we hypothesized that they could be involved in cardiac remodeling and reverse remodeling as occurs during aortic stenosis and after aortic valve replacement. Thus, in a well-characterized aortic banding-debanding mouse model, we examined the SLRPs decorin and lumican and enzymes responsible for synthesis of their glycosaminoglycan (GAG) chains. Four weeks after banding of the ascending aorta, mice were subjected to a debanding operation (DB) and were subsequently followed for 3 or 14 days. Sham-operated mice served as controls. Western blotting revealed a 2.5-fold increase in the protein levels of glycosylated decorin in mice with left ventricular pressure overload after aortic banding (AB) with a gradual decrease after DB. Interestingly, protein levels of three key enzymes responsible for decorin GAG chain synthesis were also increased after AB, two of them gradually declining after DB. The inflammatory chemokine (C-X-C motif) ligand 16 (CXCL16) was increased after AB but was not significantly altered following DB. In cardiac fibroblasts CXCL16 increased the expression of the GAG-synthesizing enzyme chondroitin polymerizing factor (CHPF). The protein levels of lumican core protein with N-linked oligosaccharides increased by sevenfold after AB and decreased again 14 days after DB. Lumican with keratan sulfate chains was not regulated. In conclusion, this study shows alterations in glycosylated decorin and lumican core protein that might be implicated in myocardial remodeling and reverse remodeling, with a potential important role for CS/DS GAG chain-synthesizing enzymes.


Assuntos
Estenose da Valva Aórtica/enzimologia , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Decorina/metabolismo , Glicosiltransferases/metabolismo , Sulfato de Queratano/metabolismo , Miocárdio/enzimologia , Remodelação Ventricular , Animais , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/imunologia , Estenose da Valva Aórtica/cirurgia , Western Blotting , Células Cultivadas , Quimiocina CXCL16 , Quimiocina CXCL6/metabolismo , Modelos Animais de Doenças , Fibroblastos/enzimologia , Fibroblastos/imunologia , Regulação Enzimológica da Expressão Gênica , Glucuronosiltransferase , Glicosilação , Glicosiltransferases/genética , Mediadores da Inflamação/metabolismo , Lumicana , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Enzimas Multifuncionais , Contração Miocárdica , Miocárdio/imunologia , Miocárdio/patologia , N-Acetilgalactosaminiltransferases/metabolismo , Fatores de Tempo , Ultrassonografia , Pressão Ventricular
9.
Scand Cardiovasc J ; 43(2): 123-8, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18781451

RESUMO

OBJECTIVES: Examine short- and intermediate-term survival after coronary artery bypass grafting (CABG) and compare this to survival of the general population and to that predicted by EuroSCORE. DESIGN: One thousand three hundred and fifty one consecutive patients undergoing CABG were prospectively included. Survival status was ascertained through the Norwegian National Registry. RESULTS: Compared to the general population, no statistical significant difference in survival was seen in operated patients. Overall mortality rate was 0.8% after 30 days, 2.8%, 4.0% and 7.1% at one, two and three years, respectively. When patients were divided into four groups according to EuroSCORE, mortality increased significantly with increasing score, as expected. However, EuroSCORE overestimated mortality. CONCLUSION: Patients operated with CABG at our institution have similar survival as in the general Norwegian population. Although overestimating mortality by almost five-fold, we found a strong association between EuroSCORE and short-time survival, and an association between EuroSCORE and intermediate-term survival.


Assuntos
Ponte de Artéria Coronária/mortalidade , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/cirurgia , Indicadores Básicos de Saúde , Idoso , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Sistema de Registros , Medição de Risco , Fatores de Tempo , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...