Asunto(s)
Disnea/diagnóstico por imagen , Defectos del Tabique Interatrial/diagnóstico por imagen , Taquicardia Supraventricular/diagnóstico por imagen , Adulto , Técnicas de Imagen Cardíaca , Disnea/complicaciones , Ecocardiografía , Femenino , Defectos del Tabique Interatrial/complicaciones , HumanosRESUMEN
It is important for primary care physicians to recognise rheumatoid arthritis and systemic lupus erythematosus patients as high-risk groups for atherosclerosis, requiring aggressive risk-factor modification. Recent studies suggest that this increased risk is not explained by an excess of traditional risk factors, but rather appears to be related to underlying rheumatic disease activity. Moreover, there is emerging data that aggressive treatment with disease-modifying agents may reduce the incidence of atherosclerosis in these conditions.
Asunto(s)
Arteriosclerosis/etiología , Artritis Reumatoide/complicaciones , Lupus Eritematoso Sistémico/complicaciones , Humanos , Factores de RiesgoRESUMEN
Although the pathogenesis of ventricular outflow tract tachycardia has not been fully elucidated, recent findings suggest that defects in cAMP signalling may be involved.
Asunto(s)
Taquicardia Ventricular/etiología , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/etiología , Comunicación Celular/fisiología , AMP Cíclico/fisiología , Humanos , Angiografía por Resonancia Magnética , Taquicardia Ventricular/diagnósticoRESUMEN
Matrix gamma-carboxyglutamic acid protein (MGP) is a mineral-binding extracellular matrix protein synthesized by vascular smooth muscle cells (VSMCs) and chondrocytes that is thought to be a key regulator of tissue calcification. In this study, we identified four polymorphisms in the promoter region of the human MGP gene. Transfection studies showed that the G-7A and T-138C polymorphisms have an important impact on in vitro promoter activity when transiently transfected into VSMCs. We found that one of these polymorphisms (T-138C) is significantly correlated with serum MGP levels in human subjects. Promoter deletion analysis showed that this polymorphism lies in a region of the promoter critical for transcription in VSMCs. This region contains a potential activating protein-1 (AP-1) binding element located between -142 and -136. We have demonstrated that the T-138C polymorphism results in altered binding of an AP-1 complex to this region. The -138T allelic variant binds AP-1 complexes consisting primarily of c-Jun, JunB and its partners Fra-1 and Fra-2 in rat VSMC. Furthermore, the -138T variant form of the promoter was induced following phorbol 12-myristate 13-acetate treatment, while the -138C variant was refractive to phorbol 12-myristate 13-acetate treatment, confirming that AP-1 factors preferentially bind to the -138T variant. This study therefore suggests that a common polymorphism of the MGP promoter influences binding of the AP-1 complex, which may lead to altered transcription and serum levels. This could have important implications for diseases such as atherosclerosis and aortic valve stenosis, since it strongly suggests a genetic basis for regulation of tissue calcification.
Asunto(s)
Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Proteínas de la Matriz Extracelular/genética , Regulación de la Expresión Génica , Polimorfismo Genético , Regiones Promotoras Genéticas , Factor de Transcripción AP-1/metabolismo , Transcripción Genética , Animales , Aorta , Sitios de Unión , Proteínas de Unión al Calcio/química , Núcleo Celular/metabolismo , Células Cultivadas , Condrocitos/metabolismo , Proteínas de la Matriz Extracelular/química , Proteínas de la Matriz Extracelular/metabolismo , Humanos , Músculo Liso Vascular/metabolismo , Polimorfismo Conformacional Retorcido-Simple , Ratas , Ratas Wistar , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Acetato de Tetradecanoilforbol/farmacología , Factor de Transcripción AP-1/química , Transfección , Proteína Gla de la MatrizRESUMEN
Matrix Gla Protein (MGP) is a small protein which is thought to be an inhibitor of tissue calcification and a regulator of cell differentiation. In this study we have examined the transcriptional regulation of MGP within rat vascular smooth muscle cells (VSMCs). We found that MGP transcription is downregulated by retinoic acid and transforming growth factor beta (TGF beta) whereas it is upregulated by vitamin D3 and cyclic AMP.
Asunto(s)
Arteriosclerosis/genética , Calcinosis/genética , Proteínas de Unión al Calcio/genética , Proteínas de la Matriz Extracelular , Transcripción Genética/genética , Animales , Colecalciferol/farmacología , AMP Cíclico/farmacología , Regulación hacia Abajo/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Músculo Liso Vascular/efectos de los fármacos , Ratas , Factor de Crecimiento Transformador beta/farmacología , Tretinoina/farmacología , Regulación hacia Arriba/efectos de los fármacos , Proteína Gla de la MatrizRESUMEN
The initiation sites for calcification in cartilage and bone are cellular products called matrix vesicles. Similar structures have been found in calcified arteries and recent studies suggest that these may be derived from apoptotic cells. It is well established that there is a link between cell death and calcification but the mechanism involved is not known. Since apoptotic cell death is known to occur in the vasculature, we set out to investigate the role of apoptosis in the initiation of vascular calcification. We used a human vascular calcification model in which postconfluent vascular smooth muscle cell (VSMC) cultures form nodules spontaneously and calcify after approximately 28 days. Our studies revealed that apoptosis occurred prior to the onset of calcification and that VSMC "blebs" or apoptotic bodies (ABs) could concentrate calcium in a crystallised form. These observations suggest that apoptosis is involved in the development of VSMC calcification and that VSMC-derived ABs have similarities with matrix vesicles.
Asunto(s)
Apoptosis/fisiología , Arteriosclerosis/patología , Calcinosis/patología , Calcio/metabolismo , Células Cultivadas , Cristalización , Humanos , Cuerpos de Inclusión/patología , Músculo Liso Vascular/patologíaAsunto(s)
Calcinosis/diagnóstico , Calcinosis/terapia , Enfermedades Vasculares/diagnóstico , Enfermedades Vasculares/terapia , Adulto , Animales , Estenosis de la Válvula Aórtica/diagnóstico , Estenosis de la Válvula Aórtica/terapia , Bioprótesis/efectos adversos , Calcinosis/etiología , Niño , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/terapia , Humanos , Medición de Riesgo , Tomografía Computarizada por Rayos X , Ultrasonografía IntervencionalRESUMEN
Traditional concepts of the pathogenesis of acute coronary syndromes have changed over the last few years. In particular it has been demonstrated that high-risk lesions are not necessarily angiographically severe. Rather, unstable high risk lesions are the ones composed of large lipid cores and thin fibrous caps. It is now widely accepted that plaque instability is related to the development of inflammation within the intima. A consequence of this is that stabilization of lesions provides a new therapeutic target. Furthermore, there is growing evidence that statins may stabilize lesions by altering the inflammatory response. A brief overview of these developments and their impact on clinical practice is presented.
Asunto(s)
Enfermedad Coronaria/etiología , Endotelio Vascular , Anticolesterolemiantes/uso terapéutico , Infecciones por Chlamydophila , Chlamydophila pneumoniae , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/inmunología , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/tratamiento farmacológico , Endotelio Vascular/inmunología , Humanos , Imagen por Resonancia Magnética , Músculo Liso Vascular/inmunología , Estrés Oxidativo , Medición de Riesgo , Vasculitis/complicaciones , Vasculitis/inmunologíaRESUMEN
Matrix Gla protein (MGP) is a mineral binding extra-cellular matrix protein which is thought to be a key inhibitor of tissue and vascular calcification. It is known to be upregulated in areas of extracellular calcification possibly to limit further harmful calcification. In this study we have demonstrated that extracellular ionic calcium (high levels of which induce calcification) is a key signal for MGP regulation and that this effect is mediated by a G protein mediated cation-sensing mechanism, functionally related to, but molecularly distinct from the calcium-sensing receptor. We therefore propose that this novel cation sensing mechanism may play a homeostatic role in preventing pathological calcification.