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1.
Crit Care ; 22(1): 314, 2018 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-30463596

RESUMEN

BACKGROUND: Iron deficiency is difficult to diagnose in critically ill patients, but may be frequent and may impair recovery. Measurement of hepcidin could help in the diagnosis of iron deficiency. We aim to assess if iron deficiency diagnosed using hepcidin is associated with poorer outcome one year after an intensive care unit stay. METHODS: We used the prospective FROG-ICU, multicentre (n = 28 ICUs), observational cohort study of critically ill survivors followed up one year after intensive care unit discharge. Iron deficiency was defined as hepcidin < 20 ng/l, ferritin < 100 ng/l or soluble transferrin receptor (sTfR)/log(ferritin) > 0.8, measured in blood drawn at intensive care unit discharge. Main outcomes were one-year all-cause mortality and poor quality of life (defined as a Short Form 36 (SF-36) score below the median). RESULTS: Among the 2087 patients in the FROG-ICU cohort, 1570 were discharged alive and 1161 had a blood sample available at intensive care unit discharge and were included in the analysis. Using hepcidin, 429 (37%) patients had iron deficiency, compared to 72 (6%) using ferritin alone and 151 (13%) using the sTfR/log(ferritin) ratio. Iron deficiency diagnosed according to low hepcidin was an independent predictor of one-year mortality (OR 1.51 (1.10-2.08)) as was high sTfR/log ferritin ratio (OR = 1.95 (1.27-3.00)), but low ferritin was not. Severe ID, defined as hepcidin < 10 ng/l, was also an independent predictor of poor one-year physical recovery (1.58 (1.01-2.49)). CONCLUSIONS: Iron deficiency, diagnosed using hepcidin, is very frequent at intensive care unit discharge and is associated with increased one-year mortality and poorer physical recovery. Whether iron treatment may improve these outcomes remains to be investigated.


Asunto(s)
Anemia Ferropénica/diagnóstico , Hepcidinas/análisis , Hierro/análisis , Alta del Paciente/estadística & datos numéricos , Calidad de Vida , Adulto , Anemia Ferropénica/epidemiología , Anemia Ferropénica/mortalidad , Distribución de Chi-Cuadrado , Estudios de Cohortes , Enfermedad Crítica/epidemiología , Enfermedad Crítica/mortalidad , Femenino , Hepcidinas/sangre , Humanos , Hierro/sangre , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Estadísticas no Paramétricas , Encuestas y Cuestionarios
2.
Circulation ; 134(13): 945-60, 2016 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-27515135

RESUMEN

BACKGROUND: Extracellular hemoglobin and cell-free heme are toxic breakdown products of hemolyzed erythrocytes. Mammals synthesize the scavenger proteins haptoglobin and hemopexin, which bind extracellular hemoglobin and heme, respectively. Transfusion of packed red blood cells is a lifesaving therapy for patients with hemorrhagic shock. Because erythrocytes undergo progressive deleterious morphological and biochemical changes during storage, transfusion of packed red blood cells that have been stored for prolonged intervals (SRBCs; stored for 35-40 days in humans or 14 days in mice) increases plasma levels of cell-free hemoglobin and heme. Therefore, in patients with hemorrhagic shock, perfusion-sensitive organs such as the kidneys are challenged not only by hypoperfusion but also by the high concentrations of plasma hemoglobin and heme that are associated with the transfusion of SRBCs. METHODS: To test whether treatment with exogenous human haptoglobin or hemopexin can ameliorate adverse effects of resuscitation with SRBCs after 2 hours of hemorrhagic shock, mice that received SRBCs were given a coinfusion of haptoglobin, hemopexin, or albumin. RESULTS: Treatment with haptoglobin or hemopexin but not albumin improved the survival rate and attenuated SRBC-induced inflammation. Treatment with haptoglobin retained free hemoglobin in the plasma and prevented SRBC-induced hemoglobinuria and kidney injury. In mice resuscitated with fresh packed red blood cells, treatment with haptoglobin, hemopexin, or albumin did not cause harmful effects. CONCLUSIONS: In mice, the adverse effects of transfusion with SRBCs after hemorrhagic shock are ameliorated by treatment with either haptoglobin or hemopexin. Haptoglobin infusion prevents kidney injury associated with high plasma hemoglobin concentrations after resuscitation with SRBCs. Treatment with the naturally occurring human plasma proteins haptoglobin or hemopexin may have beneficial effects in conditions of severe hemolysis after prolonged hypotension.


Asunto(s)
Eritrocitos/efectos de los fármacos , Haptoglobinas/farmacología , Hemopexina/farmacología , Animales , Proteínas Sanguíneas/farmacología , Eritrocitos/metabolismo , Haptoglobinas/administración & dosificación , Hemopexina/administración & dosificación , Humanos , Inflamación/tratamiento farmacológico , Ratones , Resucitación/métodos , Choque Hemorrágico/metabolismo , Reacción a la Transfusión
3.
Am J Physiol Heart Circ Physiol ; 310(8): H984-94, 2016 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-26873969

RESUMEN

Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy. However, the identity of the BMP type I receptor involved in cardiac hypertrophy and the underlying molecular mechanisms are poorly understood. By using quantitative PCR and immunoblotting, we demonstrated that BMP signaling increased during phenylephrine-induced hypertrophy in cultured neonatal rat cardiomyocytes (NRCs), as evidenced by increased phosphorylation of Smads 1 and 5 and induction of Id1 gene expression. Inhibition of BMP signaling with LDN193189 or noggin, and silencing of Smad 1 or 4 using small interfering RNA diminished the ability of phenylephrine to induce hypertrophy in NRCs. Conversely, activation of BMP signaling with BMP2 or BMP4 induced hypertrophy in NRCs. Luciferase reporter assay further showed that BMP2 or BMP4 treatment of NRCs repressed atrogin-1 gene expression concomitant with an increase in calcineurin protein levels and enhanced activity of nuclear factor of activated T cells, providing a mechanism by which BMP signaling contributes to cardiac hypertrophy. In a model of cardiac hypertrophy, C57BL/6 mice treated with angiotensin II (A2) had increased BMP signaling in the left ventricle. Treatment with LDN193189 attenuated A2-induced cardiac hypertrophy and collagen deposition in left ventricles. Cardiomyocyte-specific deletion of BMP type I receptor ALK2 (activin-like kinase 2), but not ALK1 or ALK3, inhibited BMP signaling and mitigated A2-induced cardiac hypertrophy and left ventricular fibrosis in mice. The results suggest that BMP signaling upregulates the calcineurin/nuclear factor of activated T cell pathway via BMP type I receptor ALK2, contributing to cardiac hypertrophy and fibrosis.


Asunto(s)
Receptores de Activinas Tipo I/metabolismo , Angiotensina II , Proteína Morfogenética Ósea 2/farmacología , Proteína Morfogenética Ósea 4/farmacología , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/metabolismo , Cardiomegalia/enzimología , Miocitos Cardíacos/enzimología , Receptores de Activinas Tipo I/deficiencia , Receptores de Activinas Tipo I/genética , Receptores de Activinas Tipo II , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/deficiencia , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Cardiomegalia/inducido químicamente , Cardiomegalia/genética , Cardiomegalia/patología , Cardiomegalia/prevención & control , Células Cultivadas , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Fibrosis , Proteína 1 Inhibidora de la Diferenciación/genética , Proteína 1 Inhibidora de la Diferenciación/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Factores de Transcripción NFATC/metabolismo , Fenilefrina/farmacología , Fosforilación , Pirazoles/farmacología , Pirimidinas/farmacología , Interferencia de ARN , Ratas Sprague-Dawley , Transducción de Señal , Proteínas Smad/genética , Proteínas Smad/metabolismo , Factores de Tiempo , Transfección
4.
Blood ; 124(13): 2116-23, 2014 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-25075125

RESUMEN

Expression of hepcidin, the hepatic hormone controlling iron homeostasis, is regulated by bone morphogenetic protein (BMP) signaling. We sought to identify which BMP type II receptor expressed in hepatocytes, ActR2a or BMPR2, is responsible for regulating hepcidin gene expression. We studied Bmpr2 heterozygous mice (Bmpr2(+/-)), mice with hepatocyte-specific deficiency of BMPR2, mice with global deficiency of ActR2a, and mice in which hepatocytes lacked both BMPR2 and ActR2a. Hepatic hepcidin messenger RNA (mRNA) levels, serum hepcidin and iron levels, and tissue iron levels did not differ in wild-type mice, Bmpr2(+/-) mice, and mice in which either BMPR2 or ActR2a was deficient. Deficiency of both BMP type II receptors markedly reduced hepatic hepcidin gene expression and serum hepcidin levels leading to severe iron overload. Iron injection increased hepatic hepcidin mRNA levels in mice deficient in either BMPR2 or ActR2a, but not in mice deficient in both BMP type II receptors. In addition, in mouse and human primary hepatocytes, deficiency of both BMPR2 and ActR2a profoundly decreased basal and BMP6-induced hepcidin gene expression. These results suggest that BMP type II receptors, BMPR2 and ActR2a, have redundant roles in the regulation of hepatic hepcidin gene expression and iron metabolism.


Asunto(s)
Receptores de Proteínas Morfogenéticas Óseas de Tipo II/metabolismo , Regulación de la Expresión Génica , Hepatocitos/metabolismo , Hepcidinas/genética , Hierro/metabolismo , Proteína 2 Relacionada con la Actina/deficiencia , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/deficiencia , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Femenino , Eliminación de Gen , Heterocigoto , Humanos , Sobrecarga de Hierro/genética , Sobrecarga de Hierro/metabolismo , Hígado/metabolismo , Hígado/patología , Ratones , Ratones Noqueados , Mutación , ARN Mensajero/genética , Transducción de Señal
5.
Blood ; 124(8): 1335-43, 2014 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-24904118

RESUMEN

Mutations in HFE are the most common cause of hereditary hemochromatosis (HH). HFE mutations result in reduced expression of hepcidin, a hepatic hormone, which negatively regulates iron absorption from the duodenum and iron release from macrophages. However, the mechanism by which HFE regulates hepcidin expression in hepatocytes is not well understood. It is known that the bone morphogenetic protein (BMP) pathway plays a central role in controlling hepcidin expression in the liver. Here we show that HFE overexpression increased Smad1/5/8 phosphorylation and hepcidin expression, whereas inhibition of BMP signaling abolished HFE-induced hepcidin expression in Hep3B cells. HFE was found to associate with ALK3, inhibiting ALK3 ubiquitination and proteasomal degradation and increasing ALK3 protein expression and accumulation on the cell surface. The 2 HFE mutants associated with HH, HFE C282Y and HFE H63D, regulated ALK3 protein ubiquitination and trafficking differently, but both failed to increase ALK3 cell-surface expression. Deletion of Hfe in mice resulted in a decrease in hepatic ALK3 protein expression. Our results provide evidence that HFE induces hepcidin expression via the BMP pathway: HFE interacts with ALK3 to stabilize ALK3 protein and increase ALK3 expression at the cell surface.


Asunto(s)
Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/metabolismo , Regulación de la Expresión Génica/fisiología , Hepcidinas/biosíntesis , Antígenos de Histocompatibilidad Clase I/metabolismo , Proteínas de la Membrana/metabolismo , Sustitución de Aminoácidos , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Células COS , Chlorocebus aethiops , Proteína de la Hemocromatosis , Células Hep G2 , Hepcidinas/genética , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Metaloproteinasas de la Matriz Secretadas/genética , Metaloproteinasas de la Matriz Secretadas/metabolismo , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Mutación Missense , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Proteínas Smad/metabolismo , Ubiquitinación/fisiología
6.
Blood ; 123(14): 2261-8, 2014 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-24501215

RESUMEN

Increased IL-6 production induces, via STAT3 phosphorylation, hepatic transcription of the gene encoding the iron-regulatory hormone, hepcidin, leading to development of anemia of chronic disease (ACD). Inhibition of bone morphogenetic protein (BMP) signaling prevents the induction of hepcidin gene expression by IL-6 and ameliorates ACD. Using mice with hepatocyte-specific deficiency of Alk2 or Alk3, we sought to identify the BMP type I receptor that participates in IL-6-mediated induction of hepcidin gene expression. Mice were injected with adenovirus specifying IL-6 (Ad.IL-6) or control adenovirus. Seventy-two hours later, serum iron concentrations and hepatic levels of STAT3 phosphorylation and hepcidin messenger RNA were measured. Additional mice were injected with recombinant murine IL-6 (mIL-6) or vehicle, and hepatic hepcidin gene expression was measured 4 hours later. Deficiency of Alk2 or Alk3 did not alter the ability of Ad.IL-6 injection to induce hepatic STAT3 phosphorylation. Ad.IL-6 increased hepatic hepcidin messenger RNA levels and decreased serum iron concentrations in Alk2- but not Alk3-deficient mice. Similarly, administration of mIL-6 induced hepatic hepcidin gene expression in Alk2- but not Alk3-deficient mice. These results demonstrate that the ability of IL-6 to induce hepatic hepcidin gene expression and reduce serum iron concentrations is dependent on the BMP type I receptor Alk3.


Asunto(s)
Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/fisiología , Regulación de la Expresión Génica , Hepcidinas/genética , Interleucina-6/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Células Hep G2 , Hepcidinas/metabolismo , Humanos , Hierro/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos
7.
Crit Care Med ; 41(11): 2492-501, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23887236

RESUMEN

OBJECTIVES: Transfusion of stored RBCs is associated with increased morbidity and mortality in trauma patients. Plasma hemoglobin scavenges nitric oxide, which can cause vasoconstriction, induce inflammation, and activate platelets. We hypothesized that transfusion of RBCs stored for prolonged periods would induce adverse effects (pulmonary vasoconstriction, tissue injury, inflammation, and platelet activation) in lambs subjected to severe hemorrhagic shock and that concurrent inhalation of nitric oxide would prevent these adverse effects. DESIGN: Animal study. SETTING: Research laboratory at the Massachusetts General Hospital, Boston, MA. SUBJECTS: Seventeen awake Polypay-breed lambs. INTERVENTIONS: Lambs were subjected to 2 hours of hemorrhagic shock by acutely withdrawing 50% of their blood volume. Lambs were resuscitated with autologous RBCs stored for 2 hours or less (fresh) or 39 ± 2 (mean ± SD) days (stored). Stored RBCs were administered with or without breathing nitric oxide (80 ppm) during resuscitation and for 21 hours thereafter. MEASUREMENTS AND MAIN RESULTS: We measured hemodynamic and oxygenation variables, markers of tissue injury and inflammation, plasma hemoglobin concentrations, and platelet activation. Peak pulmonary arterial pressure was higher after resuscitation with stored than with fresh RBCs (24 ± 4 vs 14 ± 2 mm Hg, p < 0.001) and correlated with peak plasma hemoglobin concentrations (R = 0.56, p = 0.003). At 21 hours after resuscitation, pulmonary myeloperoxidase activity was higher in lambs resuscitated with stored than with fresh RBCs (11 ± 2 vs 4 ± 1 U/g, p = 0.007). Furthermore, transfusion of stored RBCs increased plasma markers of tissue injury and sensitized platelets to adenosine diphosphate activation. Breathing nitric oxide prevented the pulmonary hypertension and attenuated the pulmonary myeloperoxidase activity, as well as tissue injury and sensitization of platelets to adenosine diphosphate. CONCLUSIONS: Our data suggest that resuscitation of lambs from hemorrhagic shock with autologous stored RBCs induces pulmonary hypertension and inflammation, which can be ameliorated by breathing nitric oxide.


Asunto(s)
Transfusión de Eritrocitos/métodos , Óxido Nítrico/uso terapéutico , Resucitación/métodos , Choque Hemorrágico/fisiopatología , Choque Hemorrágico/terapia , Animales , Transfusión de Eritrocitos/efectos adversos , Expresión Génica , Hemodinámica , Hipertensión Pulmonar/etiología , Pulmón/metabolismo , Neutrófilos/metabolismo , Óxido Nítrico/efectos adversos , Peroxidasa/metabolismo , Oveja Doméstica
8.
Blood ; 118(15): 4224-30, 2011 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-21841161

RESUMEN

Bone morphogenetic protein (BMP) signaling induces hepatic expression of the peptide hormone hepcidin. Hepcidin reduces serum iron levels by promoting degradation of the iron exporter ferroportin. A relative deficiency of hepcidin underlies the pathophysiology of many of the genetically distinct iron overload disorders, collectively termed hereditary hemochromatosis. Conversely, chronic inflammatory conditions and neoplastic diseases can induce high hepcidin levels, leading to impaired mobilization of iron stores and the anemia of chronic disease. Two BMP type I receptors, Alk2 (Acvr1) and Alk3 (Bmpr1a), are expressed in murine hepatocytes. We report that liver-specific deletion of either Alk2 or Alk3 causes iron overload in mice. The iron overload phenotype was more marked in Alk3- than in Alk2-deficient mice, and Alk3 deficiency was associated with a nearly complete ablation of basal BMP signaling and hepcidin expression. Both Alk2 and Alk3 were required for induction of hepcidin gene expression by BMP2 in cultured hepatocytes or by iron challenge in vivo. These observations demonstrate that one type I BMP receptor, Alk3, is critically responsible for basal hepcidin expression, whereas 2 type I BMP receptors, Alk2 and Alk3, are required for regulation of hepcidin gene expression in response to iron and BMP signaling.


Asunto(s)
Receptores de Activinas Tipo I/metabolismo , Péptidos Catiónicos Antimicrobianos/biosíntesis , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/metabolismo , Eliminación de Gen , Regulación de la Expresión Génica , Hepatocitos/metabolismo , Sobrecarga de Hierro/metabolismo , Receptores de Activinas Tipo I/genética , Animales , Péptidos Catiónicos Antimicrobianos/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Células Cultivadas , Hepcidinas , Sobrecarga de Hierro/genética , Ratones , Ratones Mutantes , Transducción de Señal/genética
9.
Crit Care Med ; 39(4): 695-701, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21220999

RESUMEN

OBJECTIVE: To compare data gathered via four different types of vascular occlusion test (VOT) by using near-infrared spectroscopy. The data may support a standardized method to appropriately measure the postischemic recovery slope, which is currently emphasized as a quantitative marker of the microvascular reserve in septic patients. DESIGN: Prospective study. SETTING: Medical intensive care unit of a university hospital. PATIENTS AND MEASUREMENTS: In 20 healthy volunteers and in 20 septic shock patients, we measured muscle tissue oxygen saturation at the thenar eminence by using near-infrared spectroscopy and performed four different vascular occlusion tests in a random order. A pneumatic cuff was placed around either the upper arm (A) or the forearm (FA). Cuff inflation was maintained either during 3 mins (VOT(A3min) and VOT(FA3min)) or until muscle tissue oxygen saturation decreased to 40% (VOT(A40%) and VOT(FA40%)). RESULTS: In volunteers: 1) During VOT(A3min) and VOT(FA3min), the minimal muscle tissue oxygen saturation was significantly higher than 40% (52% ± 10% and 54% ± 6%, respectively), and 2) the muscle tissue oxygen saturation recovery slopes were steeper with VOT(A40%) and VOT(FA40%) than with VOT(A3min) and VOT(FA3min), respectively. Considering the pooled data obtained during VOT(A3min) and VOT(FA3min) (n = 40), recovery slope negatively correlated with minimal muscle tissue oxygen saturation in volunteers (r² = .46, p < .0001) as in septic patients (r² = .34, p = .0001). Considering the pooled data obtained during 40% VOTs, the recovery slope did not correlate with ischemic time in either group. The overlap of recovery slopes between volunteers and septic patients was small for both 40% VOTs but large for both 3-min occlusion VOTs. CONCLUSION: The comparison of recovery slopes between volunteers and septic patients and the fact that the recovery slope was influenced by the extent of muscle tissue oxygen saturation decrease during ischemia and not by the ischemic time both support the use of a fixed minimal muscle tissue oxygen saturation target (40%) over the use of a fixed ischemic time (3 mins) for assessing reactive hyperemia by using near-infrared spectroscopy.


Asunto(s)
Hiperemia/diagnóstico , Espectroscopía Infrarroja Corta , Adulto , Femenino , Humanos , Hiperemia/fisiopatología , Masculino , Microcirculación/fisiología , Persona de Mediana Edad , Músculo Esquelético/irrigación sanguínea , Oxígeno/sangre , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Choque Séptico/fisiopatología , Espectroscopía Infrarroja Corta/métodos
11.
J Clin Invest ; 126(1): 389-401, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26657863

RESUMEN

Iron homeostasis is tightly regulated by the membrane iron exporter ferroportin and its regulatory peptide hormone hepcidin. The hepcidin/ferroportin axis is considered a promising therapeutic target for the treatment of diseases of iron overload or deficiency. Here, we conducted a chemical screen in zebrafish to identify small molecules that decrease ferroportin protein levels. The chemical screen led to the identification of 3 steroid molecules, epitiostanol, progesterone, and mifepristone, which decrease ferroportin levels by increasing the biosynthesis of hepcidin. These hepcidin-inducing steroids (HISs) did not activate known hepcidin-inducing pathways, including the BMP and JAK/STAT3 pathways. Progesterone receptor membrane component-1 (PGRMC1) was required for HIS-dependent increases in hepcidin biosynthesis, as PGRMC1 depletion in cultured hepatoma cells and zebrafish blocked the ability of HISs to increase hepcidin mRNA levels. Neutralizing antibodies directed against PGRMC1 attenuated the ability of HISs to induce hepcidin gene expression. Inhibiting the kinases of the SRC family, which are downstream of PGRMC1, blocked the ability of HISs to increase hepcidin mRNA levels. Furthermore, HIS treatment increased hepcidin biosynthesis in mice and humans. Together, these data indicate that PGRMC1 regulates hepcidin gene expression through an evolutionarily conserved mechanism. These studies have identified drug candidates and potential therapeutic targets for the treatment of diseases of abnormal iron metabolism.


Asunto(s)
Hepcidinas/biosíntesis , Proteínas de la Membrana/fisiología , Receptores de Progesterona/fisiología , Androstanoles/farmacología , Animales , Proteínas Morfogenéticas Óseas/fisiología , Proteínas de Transporte de Catión/análisis , Proteínas de Transporte de Catión/genética , Femenino , Regulación de la Expresión Génica , Células Hep G2 , Hepcidinas/genética , Humanos , Ratones , Mifepristona/farmacología , Progesterona/farmacología , Factor de Transcripción STAT3/fisiología , Transducción de Señal , Pez Cebra
13.
PLoS One ; 10(1): e0117098, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25603410

RESUMEN

OBJECTIVE: Matrix Gla protein (MGP) is reported to inhibit bone morphogenetic protein (BMP) signal transduction. MGP deficiency is associated with medial calcification of the arterial wall, in a process that involves both osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) and mesenchymal transition of endothelial cells (EndMT). In this study, we investigated the contribution of BMP signal transduction to the medial calcification that develops in MGP-deficient mice. APPROACH AND RESULTS: MGP-deficient mice (MGP(-/-)) were treated with one of two BMP signaling inhibitors, LDN-193189 or ALK3-Fc, beginning one day after birth. Aortic calcification was assessed in 28-day-old mice by measuring the uptake of a fluorescent bisphosphonate probe and by staining tissue sections with Alizarin red. Aortic calcification was 80% less in MGP(-/-) mice treated with LDN-193189 or ALK3-Fc compared with vehicle-treated control animals (P<0.001 for both). LDN-193189-treated MGP(-/-) mice survived longer than vehicle-treated MGP(-/-) mice. Levels of phosphorylated Smad1/5 and Id1 mRNA (markers of BMP signaling) did not differ in the aortas from MGP(-/-) and wild-type mice. Markers of EndMT and osteogenesis were increased in MGP(-/-) aortas, an effect that was prevented by LDN-193189. Calcification of isolated VSMCs was also inhibited by LDN-193189. CONCLUSIONS: Inhibition of BMP signaling leads to reduced vascular calcification and improved survival in MGP(-/-) mice. The EndMT and osteogenic transdifferentiation associated with MGP deficiency is dependent upon BMP signaling. These results suggest that BMP signal transduction has critical roles in the development of vascular calcification in MGP-deficient mice.


Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Calcificación Vascular/tratamiento farmacológico , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Proteínas de Unión al Calcio/genética , Proteínas de la Matriz Extracelular/genética , Técnica del Anticuerpo Fluorescente , Ratones , Ratones Noqueados , Pirazoles/farmacología , Pirazoles/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Calcificación Vascular/genética , Proteína Gla de la Matriz
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