RESUMEN
An association between high serum calcium/phosphate and cardiovascular events or death is well-established. However, a mechanistic explanation of this correlation is lacking. Here, we examined the role of calciprotein particles (CPPs), nanoscale bodies forming in the human blood upon its supersaturation with calcium and phosphate, in cardiovascular disease. The serum of patients with coronary artery disease or cerebrovascular disease displayed an increased propensity to form CPPs in combination with elevated ionised calcium as well as reduced albumin levels, altogether indicative of reduced Ca2+-binding capacity. Intravenous administration of CPPs to normolipidemic and normotensive Wistar rats provoked intimal hyperplasia and adventitial/perivascular inflammation in both balloon-injured and intact aortas in the absence of other cardiovascular risk factors. Upon the addition to primary human arterial endothelial cells, CPPs induced lysosome-dependent cell death, promoted the release of pro-inflammatory cytokines, stimulated leukocyte adhesion, and triggered endothelial-to-mesenchymal transition. We concluded that CPPs, which are formed in the blood as a result of altered mineral homeostasis, cause endothelial dysfunction and vascular inflammation, thereby contributing to the development of cardiovascular disease.
Asunto(s)
Angina de Pecho/fisiopatología , Isquemia Encefálica/fisiopatología , Cloruro de Calcio/sangre , Enfermedad de la Arteria Coronaria/fisiopatología , Células Endoteliales/patología , Infarto del Miocardio/fisiopatología , Fosfatos/sangre , Angina de Pecho/sangre , Angina de Pecho/genética , Animales , Aorta/metabolismo , Aorta/patología , Isquemia Encefálica/sangre , Isquemia Encefálica/genética , Cloruro de Calcio/química , Estudios de Casos y Controles , Muerte Celular , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/genética , Células Endoteliales/metabolismo , Transición Epitelial-Mesenquimal , Floculación , Regulación de la Expresión Génica , Humanos , Inflamación , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Leucocitos/metabolismo , Leucocitos/patología , Lisosomas/metabolismo , Lisosomas/patología , Masculino , Infarto del Miocardio/sangre , Infarto del Miocardio/genética , Fosfatos/química , Cultivo Primario de Células , Ratas , Ratas Wistar , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Túnica Íntima/metabolismo , Túnica Íntima/patología , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Calcium phosphate bions (CPB) are biomimetic mineralo-organic nanoparticles which represent a physiological mechanism regulating the function, transport and disposal of calcium and phosphorus in the human body. We hypothesised that CPB may be pathogenic entities and even a cause of cardiovascular calcification. Here we revealed that CPB isolated from calcified atherosclerotic plaques and artificially synthesised CPB are morphologically and chemically indistinguishable entities. Their formation is accelerated along with the increase in calcium salts-phosphates/serum concentration ratio. Experiments in vitro and in vivo showed that pathogenic effects of CPB are defined by apoptosis-mediated endothelial toxicity but not by direct tissue calcification or functional changes in anti-calcification proteins. Since the factors underlying the formation of CPB and their pathogenic mechanism closely resemble those responsible for atherosclerosis development, further research in this direction may help us to uncover triggers of this disease.
Asunto(s)
Materiales Biomiméticos/farmacología , Fosfatos de Calcio/toxicidad , Células Endoteliales/citología , Placa Aterosclerótica/química , Apoptosis , Calcificación Fisiológica/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Humanos , Fosfatos/metabolismo , Sales (Química)/metabolismoRESUMEN
Critical thicknesses of two-dimensional to three-dimensional growth in GexSi1-x layers were measured as a function of composition for different growth temperatures. In addition to the (2 × 1) superstructure for a Ge film grown on Si(100), the GexSi1-x layers are characterized by the formation of (2 × n) reconstruction. We measured n for all layers of Ge/GexSi1-x/Ge heterosystem using our software with respect to the video recording of reflection high-energy electron diffraction (RHEED) pattern during growth. The n reaches a minimum value of about 8 for clear Ge layer, whereas for GexSi1-x films, n is increased from 8 to 14. The presence of a thin strained film of the GexSi1-x caused not only the changes in critical thicknesses of the transitions, but also affected the properties of the germanium nanocluster array for the top Ge layer. Based on the RHEED data, the hut-like island form, which has not been previously observed by us between the hut and dome islands, has been detected. Data on the growth of Ge/GexSi1-x/Ge heterostructures with the uniform array of islands in the second layer of the Ge film have been received.