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The association between matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs) and obesity as well as obesity-related disease including metabolic syndrome is not fully explored. Our aims are that: (i) to evaluate the plasma levels of MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2 and their ratios in non-obese people, overweight and obese people with or without metabolic syndrome, (ii) to investigate correlations between MMPs or TIMPs levels and several anthropometric parameters, blood pressure, endothelial function. Anthropometric and biochemical parameters were determined in 479 randomly selected participants, subdividing according to body mass index (BMI) and metabolic syndrome status. Plasma MMPs and TIMPs levels were measured. The assessment of endothelial function was characterized in people with obesity, overweight and non-obese, using laser Doppler Flowmetry. Obese people have elevated MMP-1, MMP-2, TIMP-1, TIMP-2 levels and decreased MMP-3/TIMP-1 and MMP-9/TIMP-1 ratios compared with non-obese people. MMP-1 levels and MMP-1/TIMP-1 ratio were positively correlated with BMI and waist circumference (WC) while MMP-2 levels were negatively correlated with BMI and WC values in obese people. MMP-3 levels and MMP-3/TIMP-1 ratio were positively correlated with systolic blood pressure (SBP) or diastolic blood pressure (DBP) in obese and metabolic syndrome people. Additionally, MMP-9 levels and MMP-9/TIMP-1 ratio were negatively correlated with endothelium-dependent response in obese and metabolic syndrome people. MMP-1, MMP-2, TIMP-1, TIMP-2 levels were increased in obese subjects. Significant correlations between anthropometric parameters and MMP-1 as well as MMP-1/TIMP-1 ratio supported these results. MMP-3 and -9 levels as well as their ratios with TIMP-1 were associated with blood pressure and endothelial-dependent response, respectively. In conclusion, our results demonstrated that MMP-1, MMP-3 and MMP-9 levels were correlated with several obesity-related parameters including BMI, WC, blood pressure and endothelial-dependent response. Our findings will hopefully provide new aspects for the use of MMPs and TIMPs as clinical biomarkers in obesity-related cardiovascular diseases such as metabolic syndrome and hypertension. The lack of measure of MMPs activity in plasma and relevant organs/tissues in obesity and metabolic syndrome is considered as a limitation in this report.
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Presión Sanguínea , Índice de Masa Corporal , Endotelio Vascular/fisiopatología , Inhibidores de la Metaloproteinasa de la Matriz/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Obesidad/patología , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Obesidad/metabolismoRESUMEN
PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. METHODS: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. RESULTS: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. CONCLUSION: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.
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Aneurisma de la Aorta Torácica , Disección Aórtica , Proteínas ADAM , Disección Aórtica/genética , Animales , Aneurisma de la Aorta Torácica/genética , Exoma/genética , Fibrilina-1/genética , Humanos , RatonesRESUMEN
Elastic fibers (90% elastin, 10% fibrillin-rich microfibrils) are synthesized only in early life and adolescence mainly by the vascular smooth muscle cells through the cross-linking of its soluble precursor, tropoelastin. Elastic fibers endow the large elastic arteries with resilience and elasticity. Normal vascular aging is associated with arterial remodeling and stiffening, especially due to the end of production and degradation of elastic fibers, leading to altered cardiovascular function. Several pharmacological treatments stimulate the production of elastin and elastic fibers. In particular, dill extract (DE) has been demonstrated to stimulate elastin production in vitro in dermal equivalent models and in skin fibroblasts to increase lysyl oxidase-like-1 (LOXL-1) gene expression, an enzyme contributing to tropoelastin crosslinking and elastin formation. Here, we have investigated the effects of a chronic treatment (three months) of aged male mice with DE (5% or 10% v/v, in drinking water) on the structure and function of the ascending aorta. DE treatment, especially at 10%, of aged mice protected pre-existing elastic lamellae, reactivated tropoelastin and LOXL-1 expressions, induced elastic fiber neo-synthesis, and decreased the stiffness of the aging aortic wall, probably explaining the reversal of the age-related cardiac hypertrophy also observed following the treatment. DE could thus be considered as an anti-aging product for the cardiovascular system.
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Envejecimiento , Aminoácido Oxidorreductasas/metabolismo , Anethum graveolens/química , Aorta/efectos de los fármacos , Cardiomegalia/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Aorta/metabolismo , Fenómenos Biomecánicos , Presión Sanguínea , Peso Corporal , Cardiomegalia/metabolismo , Fibroblastos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Tamaño de los Órganos , Extractos Vegetales/química , ARN/metabolismo , Piel/metabolismo , Tropoelastina/metabolismoRESUMEN
This Thematic Minireview Series of Matrix Biology focused on elastin, from structure to disease celebrates the memory of Ladislas Robert, a pioneer in Matrix Biology in France and Europe. Since his first publication on elastin and elastases in 1957, the huge development in matrix biology led to major findings on elastic fibers and their component proteins including elastin architecture, the role of fibrillins and microfibril-binding proteins on elastin assembly, the effects of sequence variants of human tropoelastin on its assembly, structure and functions, the role of elastin peptides in health and diseases, the identification of neuraminidase-1 as a member of the elastin receptor complex, and the fate of elastic fibers upon aging, which are reviewed in this series. Two other reviews, focused on the design and use of elastin-like recombinamers as biomaterials, and on the circadian rhythms in skin and other elastic tissues, complete this series.
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Elastina/genética , Elastina/metabolismo , Matriz Extracelular/metabolismo , Elastina/química , Variación Genética , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Neuraminidasa/química , Neuraminidasa/genética , Neuraminidasa/metabolismo , Tropoelastina/química , Tropoelastina/genética , Tropoelastina/metabolismoRESUMEN
In the arteries of vertebrates, evolution has given rise to resilient macromolecular structures, elastin and elastic fibers, capable of sustaining an elevated blood pressure and smoothening the discontinuous blood flow and pressure generated by the heart. Elastic fibers are produced only during development and childhood, before being progressively degraded by mechanical stress and enzymatic activities during adulthood and aging. During this period, arterial elastic fiber calcification and loading of lipids also occur, all of these events conducting to arteriosclerosis. This leads to a progressive dysfunction of the large elastic arteries inducing elevated blood pressure as well as altered hemodynamics and organ perfusion, which induce more global malfunctions of the body during normal aging. Additionally, some arterial conditions occur more frequently with advancing age, such as atherosclerosis or aneurysms, which are called age-related diseases or pathological aging. The physiological or pathological degradation of elastic fibers and function of elastic arteries seemed to be rather inevitable over time. However, during the recent years, different molecules - including several ATP-dependent potassium channel openers, such as minoxidil - have been shown to re-induce elastin production and elastic fiber assembly, leading to improvements in the arterial structure and function or in organ perfusion. This review summarizes the changes in the arterial elastic fibers and structure from development until aging, and presents some of the potential pharmacotherapies leading to elastic fiber neosynthesis and arterial function improvement.
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Envejecimiento/fisiología , Arterias/fisiología , Elastina/metabolismo , Envejecimiento/efectos de los fármacos , Animales , Arterias/química , Arterias/efectos de los fármacos , Elastina/química , Elastina/efectos de los fármacos , Matriz Extracelular/química , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Humanos , Minoxidil/farmacología , Estrés MecánicoRESUMEN
Marfan syndrome (MFS) is a rare autosomal dominant connective tissue disorder related to variants in the FBN1 gene. Prognosis is related to aortic risk of dissection following aneurysm. MFS clinical variability is notable, for age of onset as well as severity and number of clinical manifestations. To identify genetic modifiers, we combined genome-wide approaches in 1070 clinically well-characterized FBN1 disease-causing variant carriers: (1) an FBN1 eQTL analysis in 80 fibroblasts of FBN1 stop variant carriers, (2) a linkage analysis, (3) a kinship matrix association study in 14 clinically concordant and discordant sib-pairs, (4) a genome-wide association study and (5) a whole exome sequencing in 98 extreme phenotype samples.Three genetic mechanisms of variability were found. A new genotype/phenotype correlation with an excess of loss-of-cysteine variants (P = 0.004) in severely affected subjects. A second pathogenic event in another thoracic aortic aneurysm gene or the COL4A1 gene (known to be involved in cerebral aneurysm) was found in nine individuals. A polygenic model involving at least nine modifier loci (named gMod-M1-9) was observed through cross-mapping of results. Notably, gMod-M2 which co-localizes with PRKG1, in which activating variants have already been described in thoracic aortic aneurysm, and gMod-M3 co-localized with a metalloprotease (proteins of extra-cellular matrix regulation) cluster. Our results represent a major advance in understanding the complex genetic architecture of MFS and provide the first steps toward prediction of clinical evolution.
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Genes Modificadores , Síndrome de Marfan/genética , Herencia Multifactorial , Fenotipo , Adolescente , Adulto , Anciano , Células Cultivadas , Colágeno Tipo IV/genética , Femenino , Fibrilina-1/genética , Fibroblastos/metabolismo , Ligamiento Genético , Humanos , Masculino , Síndrome de Marfan/patología , Persona de Mediana Edad , Mutación , Sitios de Carácter CuantitativoRESUMEN
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that displays a great clinical variability. Previous work in our laboratory showed that fibrillin-1 (FBN1) messenger RNA (mRNA) expression is a surrogate endpoint for MFS severity. Therefore, an expression quantitative trait loci (eQTL) analysis was performed to identify trans-acting regulators of FBN1 expression, and a significant signal reached genome-wide significant threshold on chromosome 11. This signal delineated a region comprising one expressed gene, SLN (encoding sarcolipin), and a single pseudogene, SNX7-ps1 (CTD-2651C21.3). We first investigated the region and then looked for association between the genes in the region and FBN1 expression. For the first time, we showed that the SLN gene is weakly expressed in skin fibroblasts. There is no direct correlation between SLN and FBN1 gene expression. We showed that calcium influx modulates FBN1 gene expression. Finally, SLN gene expression is highly correlated to that of the neighboring SNX7-ps1. We were able to confirm the impact of calcium influx on FBN1 gene expression but we could not conclude regarding the role of sarcolipin and/or the eQTL locus in this regulation.
RESUMEN
BACKGROUND: Recent evidence suggests that adaptive immunity develops during abdominal aortic aneurysm evolution. Uncertainties remain about the antigens implicated and their role in inducing rupture. Because antigens from the extracellular matrix (ECM) have been suspected, the aim of this experimental study was to characterize the role of adaptive immunity directed against antigens from the aortic ECM. METHODS: In a first step, an experimental model of abdominal aortic aneurysm rupture based on adaptive immunity against the ECM was developed and characterized. Forty 4-week-old male Lewis rats were divided into two groups. In the ECM group (n = 20), rats were presensitized against the guinea pig aortic ECM before implantation of a decellularized aortic xenograft (DAX). In the control group (n = 20), rats were not presensitized before DAX implantation. In each group, half the rats were sacrificed at day 3 to analyze early mechanisms involved after DAX implantation. In a second step, we aimed to assess which ECM component was most efficient in inducing rupture. For this purpose, the nonfibrillar and fibrillar ECM components were sequentially extracted from the guinea pig aortic wall. Forty Lewis rats were then divided into four groups. Each group was presensitized against one ECM component (structural glycoproteins and proteoglycans, collagen, elastin alone, and elastin-associated glycoproteins) before DAX implantation. Apart from those that experienced rupture, rats were sacrificed at day 21. Xenografts were harvested for histologic, immunofluorescence, and conditioned medium analyses. RESULTS: In total, early aortic rupture occurred in 80% of the ECM group vs 0% of the control group (P < .001). In the ECM group, major circumferential immunoglobulin deposits were observed in combination with the C3 complement fraction, without cell infiltration. Conditioned medium analysis revealed that matrix metalloproteinase 9 and myeloperoxidase levels and elastase activities were significantly increased in this group. Immunofluorescence analysis demonstrated that myeloperoxidase co-localized with tissue-free DNA and histone H4, highlighting local neutrophil activation and formation of neutrophil extracellular traps. Following differential presensitization, it appeared that rats presensitized against structural glycoproteins and proteoglycans were significantly more susceptible to rupture after DAX implantation. CONCLUSIONS: Stimulating adaptive immunity against the aortic ECM, especially structural glycoproteins and proteoglycans, triggers rupture after DAX implantation. Further studies are needed to assess the precise proteins involved.
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Anticuerpos/inmunología , Antígenos/inmunología , Aorta/inmunología , Aneurisma de la Aorta Abdominal/inmunología , Rotura de la Aorta/inmunología , Proteínas de la Matriz Extracelular/inmunología , Matriz Extracelular/inmunología , Inmunidad Humoral , Animales , Aorta/metabolismo , Aorta/patología , Aorta/trasplante , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Rotura de la Aorta/metabolismo , Rotura de la Aorta/patología , Complemento C3/inmunología , Modelos Animales de Enfermedad , Matriz Extracelular/metabolismo , Matriz Extracelular/trasplante , Trampas Extracelulares/inmunología , Trampas Extracelulares/metabolismo , Cobayas , Xenoinjertos , Histonas/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Activación Neutrófila , Neutrófilos/inmunología , Neutrófilos/metabolismo , Elastasa Pancreática/metabolismo , Peroxidasa/metabolismo , Ratas Endogámicas LewRESUMEN
AIM: To investigate whether plasma concentrations of proprotein-convertase-subtilisin/kexin type 9 (PCSK9) were associated with cardiovascular (CV) events in two cohorts of patients with type 2 diabetes mellitus. METHODS: We considered patients from the DIABHYCAR (n = 3137) and the SURDIAGENE (n = 1468) studies. Baseline plasma PCSK9 concentration was measured using an immunofluorescence assay. In post hoc, but preplanned, analyses we assessed the relationship between PCSK9 and the following endpoints: (1) a combined endpoint of major CV events: CV death, non-fatal myocardial infarction (MI), stroke and heart failure-related hospital admission; (2) a composite of all CV events: MI, stroke, heart failure-related hospital admission, coronary/peripheral angioplasty or bypass, CV death; (3) MI; (4) stroke/transient ischaemic attack (TIA); and (5) CV death. RESULTS: In the DIABHYCAR study, plasma PCSK9 tertiles were associated with the incidence of MI, all CV events and stroke/TIA (P for trend <.05). In adjusted Cox analysis, plasma PCSK9 was associated, independently of classic risk factors, with the incidence of major CV events (hazard ratio [HR] for 1-unit increase of log[PCSK9] 1.28 [95% confidence interval {CI} 1.06-1.55]), the incidence of MI (HR 1.66 [95% CI 1.05-2.63]), and the incidence of all CV events (HR 1.22 [95% CI 1.04-1.44]), but not with CV death. Plasma PCSK9 was not associated with the incidence of CV disease in the participants of the SURDIAGENE study with high CV risk treated with statins and insulin. CONCLUSIONS: We found that PCSK9 was inconsistently associated with CV events in populations with type 2 diabetes. The association may depend on the level of CV risk and the background treatment.
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Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/sangre , Proproteína Convertasa 9/sangre , Anciano , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Estudios de Cohortes , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/terapia , Angiopatías Diabéticas/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangre , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/epidemiología , Factores de RiesgoRESUMEN
BACKGROUND AND AIMS: The arterial wall calcium score and circulating free DNA levels are now used in clinical practice as biomarkers of cardiovascular risk. Calcium phosphate apatite retention in the arterial wall necessitates precipitation on an anionic platform. Here, we explore the role of tissue-free DNA as such a platform. METHODS: The first step consisted of histological observation of samples from human and rat calcified arteries. Various stains were used to evaluate colocalization of free DNA with calcified tissue (alizarin red, fluorescent Hoechst, DNA immunostaining and TUNEL assay). Sections were treated by EDTA to reveal calcification background. Secondly, a rat model of vascular calcifications induced by intra-aortic infusions of free DNA and elastase + free DNA was developed. Rat aortas underwent a micro-CT for calcium score calculation at 3 weeks. Rat and human calcifications were qualitatively characterized using µFourier Transform Infrared Spectroscopy (µFTIR) and Field Emission-Scanning Electron Microscopy (FE-SEM). RESULTS: Our histological study shows colocalization of calcified arterial plaques with free DNA. In the intra-aortic infusion model, free DNA was able to penetrate into the arterial wall and induce calcifications whereas no microscopic calcification was seen in control aortas. The calcification score in the elastase + free DNA group was significantly higher than in the control groups. Qualitative evaluation with µFTIR and FE-SEM demonstrated typical calcium phosphate retention in human and rat arterial specimens. CONCLUSIONS: This translational study demonstrates that free DNA could be involved in arterial calcification formation by precipitating calcium phosphate apatite crystals in the vessel wall.
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Apatitas/metabolismo , Arterias/metabolismo , Ácidos Nucleicos Libres de Células/metabolismo , ADN/metabolismo , Calcificación Vascular/metabolismo , Animales , Arterias/diagnóstico por imagen , Arterias/ultraestructura , Fosfatos de Calcio , Ácidos Nucleicos Libres de Células/genética , Cristalización , ADN/genética , Modelos Animales de Enfermedad , Humanos , Microscopía Electrónica de Rastreo , Ratas , Espectroscopía Infrarroja por Transformada de Fourier , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/genética , Calcificación Vascular/patología , Microtomografía por Rayos XRESUMEN
Normal arterial aging processes involve vascular cell dysfunction associated with wall stiffening, the latter being due to progressive elastin and elastic fiber degradation, and elastin and collagen cross-linking by advanced glycation end products (AGEs). These processes progressively lead to cardiovascular dysfunction during aging. Elastin is only synthesized during late gestation and childhood, and further degradation occurring throughout adulthood cannot be physiologically compensated by replacement of altered material. However, the ATP-dependent K+ channel opener minoxidil has been shown to stimulate elastin expression in vitro and in vivo in the aorta of young adult rats. Therefore, we have studied the effect of a 10-week chronic oral treatment with minoxidil (120 mg/L in drinking water) on the aortic structure and function in aged 24-month-old mice. Minoxidil treatment increased tropoelastin, fibulin-5, and lysyl-oxidase messenger RNA levels, reinduced a moderate expression of elastin, and lowered the levels of AGE-related molecules. This was accompanied by the formation of newly synthesized elastic fibers, which had diverse orientations in the wall. A decrease in the glycation capacity of aortic elastin was also produced by minoxidil treatment. The ascending aorta also underwent a minoxidil-induced increase in diameter and decrease in wall thickness, which partly reversed the age-associated thickening and returned the wall thickness value and strain-stress relation closer to those of younger adult animals. In conclusion, our results suggest that minoxidil presents an interesting potential for arterial remodeling in an antiaging perspective, even when treating already aged animals.
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Envejecimiento/fisiología , Aorta/fisiología , Tejido Elástico/fisiología , Minoxidil/farmacología , Envejecimiento/efectos de los fármacos , Animales , Aorta/citología , Aorta/efectos de los fármacos , Aorta/ultraestructura , Fenómenos Biomecánicos/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Colágeno/genética , Colágeno/metabolismo , Tejido Elástico/efectos de los fármacos , Elastina/metabolismo , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Masculino , Ratones Endogámicos C57BL , Tamaño de los Órganos/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
AIMS: The impact of MMP-1 (-519A/G, -1607 1G/2G), MMP-3 Lys45Glu (A/G), MMP-7 -181A/G, and MMP-12 -82A/G variants and plasma MMP levels on obesity and microvascular reactivity in Tunisians. METHODS: Our population included 202 nonobese and 168 obese subjects. Anthropometric, biochemical, and microvascular parameters were determined according to standard protocols. PCR-RFLP and ELISA were used to determine the genetic variants and levels of MMPs, respectively. RESULTS: The MMP-3 45Glu (G) allele associates with higher anthropometric values and MMP-3 levels compared to AA genotype carriers (BMI (kg/m2): 30 ± 0.51 versus 27.33 ± 0.8, P = 0.004; MMP-3 levels: 7.45 (4.77-11.91) versus 5.21 (3.60-10.21) ng/ml, P = 0.006). The MMP-12 -82G allele was also associated with higher BMI values when compared to subjects carrying the AA genotype (31.41 ± 0.85 versus 28.76 ± 0.43, P < 0.001). Individuals carrying the MMP-3 45G or MMP-12 -82G variants were also associated with a higher risk for severe forms of obesity (MMP-3: OR = 1.9, P = 0.002; MMP-12: OR = 2.63, P = 0.003). Similarly, the MMP-7 -181G allele was associated with a higher MMP-7 level and an increased risk for morbid obesity when compared to AA genotype carriers (0.32 (0.31-0.60) versus 0.18 (0.17-0.24) ng/ml, P = 0.01; OR = 1.67, P = 0.02, resp.). CONCLUSION: MMP-3, MMP-7, and MMP-12 polymorphisms associate with obesity risk and its severity.
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Metaloproteinasas de la Matriz/genética , Obesidad/genética , Polimorfismo de Nucleótido Simple , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Metaloproteinasas de la Matriz/sangre , Microvasos/fisiología , Obesidad/sangre , Fenotipo , VasodilataciónRESUMEN
Hydrogen sulfide (H2S) is a mediator with demonstrated protective effects for the cardiovascular system. On the other hand, prostaglandin (PG)E2 is involved in vascular wall remodeling by regulating matrix metalloproteinase (MMP) activities. We tested the hypothesis that endogenous H2S may modulate PGE2, MMP-1 activity and endogenous tissue inhibitors of MMPs (TIMP-1/-2). This regulatory pathway could be involved in thinning of abdominal aortic aneurysm (AAA) and thickening of saphenous vein (SV) varicosities. The expression of the enzyme responsible for H2S synthesis, cystathionine-γ-lyase (CSE) and its activity, were significantly higher in varicose vein as compared to SV. On the contrary, the endogenous H2S level and CSE expression were lower in AAA as compared to healthy aorta (HA). Endogenous H2S was responsible for inhibition of PGE2 synthesis mostly in varicose veins and HA. A similar effect was observed with exogenous H2S and consequently decreasing active MMP-1/TIMP ratios in SV and varicose veins. In contrast, in AAA, higher levels of PGE2 and active MMP-1/TIMP ratios were found versus HA. These findings suggest that differences in H2S content in AAA and varicose veins modulate endogenous PGE2 production and consequently the MMP/TIMP ratio. This mechanism may be crucial in vascular wall remodeling observed in different vascular pathologies (aneurysm, varicosities, atherosclerosis and pulmonary hypertension).
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Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta/metabolismo , Dinoprostona/metabolismo , Metaloproteasas/metabolismo , Vena Safena/metabolismo , Sulfitos/metabolismo , Várices/metabolismo , Anciano , Aneurisma de la Aorta/patología , Aneurisma de la Aorta Abdominal/patología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vena Safena/patología , Transducción de Señal/fisiología , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Várices/patologíaRESUMEN
BACKGROUND: The aim of this study was to determine the plasmatic levels matrix metalloproteinases (MMPs): MMP-2, MMP-3, MMP-9, and their inhibitors (TIMPs): TIMP-1 and TIMP-2 in hypertensive patients and healthy subjects. METHODS: The study involved 60 hypertensive patients and 61 adult healthy controls. Pro-MMP-9 and pro-MMP-2 activity was determined by the gelatin zymography method and MMP-3, TIMP-1, and TIMP-2 levels were determined by ELISA method. RESULTS: The mean plasma activity of pro-MMP-9 in the hypertensive group and the control group were significantly different (153.33 ± 129.33 vs. 90.38 ± 97.49 x 10(3) densitometric units/µL; p < 0.01). MMP-3 plasmatic level was significantly higher in hypertensive subjects than healthy subjects (20.24 ± 8.63 vs. 16.41 ± 6.8 ng/mL; p < 0.05), whereas the plasma concentration of TIMP-1 in the hypertensive group was lower than the control group 88.96 ± 26.9 vs. 93.96 ± 27.28 ng/mL. The MMP-3/ TIMP-1 and the MMP-3/TMP-2 ratios were higher in hypertensive subjects than healthy subjects. Also, we have found a significant positive correlation between systolic blood pressure and pro-MMP-9 (r = 0.311, p < 0.001). CONCLUSIONS: The present study identified the existence of abnormalities in plasma markers for extracellular matrix metabolism in hypertensive patients.
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Hipertensión/metabolismo , Metaloproteasas/sangre , Inhibidor Tisular de Metaloproteinasa-1/sangre , Inhibidor Tisular de Metaloproteinasa-2/sangre , Adulto , Humanos , Metaloproteinasa 2 de la Matriz/sangre , Metaloproteinasa 3 de la Matriz/sangre , Persona de Mediana EdadRESUMEN
Haploinsufficiency of elastin leads, in more than half of patients with Williams-Beuren syndrome, to development of supravalvular aortic stenosis and hypertension. Determining mechanisms implicated in elastin synthesis would be of interest to find new elastogenic molecules to treat such a pathology. Here, we analyzed the signaling pathway linking intracellular calcium concentration to elastin regulation to find new molecules able to increase elastin synthesis. Their elastogenic ability was then investigated, in vitro and in vivo, using inhibitors of the highlighted pathway. The Brown Norway rat strain was used here as an arterial elastin-deficient model. Our data indicated that A23187, a calcium ionophore, decreases elastin expression in cultured vascular smooth muscle cells, both transcriptionally and post-transcriptionally. Addition of A23187 induced transient activation of extracellular signal-regulated kinases 1/2, leading to an upregulation of activator protein-1 transcription factors, which correlated with the inhibition of elastin gene transcription. Pretreatment with U0126, an inhibitor of extracellular signal-regulated kinases 1/2 phosphorylation, abolished the inhibition of elastin gene transcription by A23187. In vitro, U0126 increased elastin synthesis and in vivo, 24 hours after an intravenous administration, elastin gene transcription and elastin mRNA levels were increased in the rat aorta. A chronic treatment, diffusing U0126 for 10 weeks, increased aortic elastin content without changing cell number and collagen content. In conclusion, calcium ionophore represses elastin gene transcription via activation of extracellular signal-regulated kinases 1/2 pathway and activator protein-1 transcription factors. Moreover, we provide strong evidence that inhibition of extracellular signal-regulated kinases 1/2 increases elastin synthesis and could thus be suitable for treating vascular pathologies characterized by diminished arterial elastin content.
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Aorta/metabolismo , Elastina/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosforilación/efectos de los fármacos , Animales , Aorta/efectos de los fármacos , Butadienos/farmacología , Calcimicina/farmacología , Calcio/metabolismo , Ionóforos de Calcio/farmacología , Inhibidores Enzimáticos/farmacología , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Nitrilos/farmacología , Ratas , Síndrome de Williams/metabolismoRESUMEN
UNLABELLED: Varicose veins are elongated and dilated saphenous veins. Despite the high prevalence of this disease, its pathogenesis remains unclear. AIMS: In this study, we investigated the control of matrix metalloproteinases (MMPs) expression by prostaglandin (PG)E2 during the vascular wall remodeling of human varicose veins. METHODS AND RESULTS: Varicose (small (SDv) and large diameter (LDv)) and healthy saphenous veins (SV) were obtained after surgery. Microsomal and cytosolic PGE-synthases (mPGES and cPGES) protein and mRNA responsible for PGE2 metabolism were analyzed in all veins. cPGES protein was absent while its mRNA was weakly expressed. mPGES-2 expression was similar in the different saphenous veins. mPGES-1 mRNA and protein were detected in healthy veins and a significant decrease was found in LDv. Additionally, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), responsible for PGE2 degradation, was over-expressed in varicose veins. These variations in mPGES-1 and 15-PGDH density account for the decreased PGE2 level observed in varicose veins. Furthermore, a significant decrease in PGE2 receptor (EP4) levels was also found in SDv and LDv. Active MMP-1 and total MMP-2 concentrations were significantly decreased in varicose veins while the tissue inhibitors of metalloproteinases (TIMP -1 and -2), were significantly increased, probably explaining the increased collagen content found in LDv. Finally, the MMP/TIMP ratio is restored by exogenous PGE2 in varicose veins and reduced in presence of an EP4 receptor antagonist in healthy veins. CONCLUSIONS: In conclusion, PGE2 could be responsible for the vascular wall thickening in human varicose veins. This mechanism could be protective, strengthening the vascular wall in order to counteract venous stasis.
Asunto(s)
Colágeno/metabolismo , Dinoprostona/metabolismo , Metaloproteinasa 1 de la Matriz/metabolismo , Várices/metabolismo , Anciano , Femenino , Humanos , Hidroxiprostaglandina Deshidrogenasas/metabolismo , Oxidorreductasas Intramoleculares/metabolismo , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Persona de Mediana Edad , Prostaglandina-E Sintasas , ARN Mensajero/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/antagonistas & inhibidores , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Vena Safena/metabolismo , Vena Safena/patología , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Várices/patologíaRESUMEN
Hypertension is a cardiovascular disorder that appears in more than half of the patients with Williams-Beuren syndrome, hemizygous for the elastin gene among 26 to 28 other genes. It was shown that the antihypertensive drug minoxidil, an ATP-dependent potassium channel opener, enhances elastic fiber formation; however, no wide clinical application was developed because of its adverse side effects. The Brown Norway rat was used here as an arterial elastin-deficient model. We tested 3 different potassium channel openers, minoxidil, diazoxide, and pinacidil, and 1 potassium channel blocker, glibenclamide, on cultured smooth muscle cells from Brown Norway rat aorta. All tested potassium channel openers increased mRNAs encoding proteins and enzymes involved in elastic fiber formation, whereas glibenclamide had the opposite effect. The higher steady-state level of tropoelastin mRNA in minoxidil-treated cells was attributable to an increase in both transcription and mRNA stability. Treatment of Brown Norway rats for 10 weeks with minoxidil or diazoxide increased elastic fiber content and decreased cell number in the aortic media, without changing collagen content. The minoxidil-induced cardiac hypertrophy was reduced when animals simultaneously received irbesartan, an angiotensin II-receptor antagonist. This side effect of minoxidil was not observed in diazoxide-treated animals. In conclusion, diazoxide, causing less undesirable side effects than minoxidil, or coadministration of minoxidil and irbesartan, increases elastic fiber content, decreases cell number in the aorta and, thus, could be suitable for treating vascular pathologies characterized by diminished arterial elastin content and simultaneous hypertension.
Asunto(s)
Aorta/efectos de los fármacos , Tejido Elástico/efectos de los fármacos , Elastina/genética , Músculo Liso Vascular/efectos de los fármacos , Canales de Potasio/metabolismo , Animales , Antihipertensivos/farmacología , Aorta/metabolismo , Presión Sanguínea/efectos de los fármacos , Diazóxido/farmacología , Tejido Elástico/metabolismo , Elastina/metabolismo , Gliburida/farmacología , Masculino , Minoxidil/farmacología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Pinacidilo/farmacología , Ratas , Ratas Endogámicas BN , Vasodilatadores/farmacologíaRESUMEN
BACKGROUND: The aim of the present study was to investigate differences of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in the peripheral blood of patients admitted with acute coronary syndrome (ACS), in correlation with the widely accepted markers of inflammatory activity, C-reactive protein, fibrinogen, and white blood cell number. METHODS: 315 patients with ACS (165 unstable angina pectoris/non-ST-elevation myocardial infarction, 150 ST-elevation myocardial infarction), 111 stable angina (SA) patients, and 296 control subjects were enrolled in the study. All biochemical analyses were carried out using a Hitachi 912 analyzer (Roche). Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were determined in citrate plasma by ELISA methods. White blood cells (WBC) and fibrinogen were also determined. RESULTS: The plasma concentrations of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, C-reactive protein, fibrinogen, and white blood cells in patients with acute coronary syndrome were significantly elevated compared to the control group (p < 0.001). MMP-9/TIMP-1 ratio was significantly higher in SA and ACS patients (p < 0.001) than controls. Strong positive associations were observed between MMP-9 and TIMP-1 (r = 0.213, p < 0.01), MMP-9 and CRP (r = 0.103, p < 0.01), MMP-9 and fibrinogen (r = 0.299, p < 0.01), MMP-9 and WBC (r = 0.135, p < 0.01), TIMP-1 and CRP (r = 0.219, p < 0.01), TIMP-1 and Fibrinogen (r = 0.226, p < 0.01), TIMP-1 and WBC (r = 0.094, p < 0.1), CRP and fibrinogen (r = 0.158, p < 0.01), CRP and WBC (r = 0.156, p < 0.01, and finally between fibrinogen and WBC (r = 0.234, p < 0.01) in the patients with ACS. CONCLUSIONS: In conclusion, our observations suggest that ACS shows an increase in both remodeling and inflammation markers. In addition, the strong relationship with MMP-9 and inflammatory mediators such as CRP, fibrinogen, and WBC in ACS patients suggests that MMP-9 might be an additional marker and/or consequence of inflammatory components in ACS.
Asunto(s)
Síndrome Coronario Agudo/sangre , Mediadores de Inflamación/sangre , Metaloproteinasa 9 de la Matriz/sangre , Inhibidor Tisular de Metaloproteinasa-1/sangre , Síndrome Coronario Agudo/enzimología , Anciano , Proteína C-Reactiva/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Fibrinógeno/metabolismo , Humanos , Masculino , Persona de Mediana Edad , TúnezRESUMEN
BACKGROUND AND AIM OF THE STUDY: Aortic stenosis, the most frequent valvulopathy in the Western world, is characterized by an important extracellular matrix (ECM) remodeling and a process of calcification in the aortic valves. One physiopathological assumption is that transforming growth factor-beta1 (TGF-beta1) acts through ECM remodeling and plays a role in calcification, implicating also microparticles (MPs). Another recent notion is the active involvement of inflammatory mediators in the calcification process of aortic stenosis. METHODS: A total of 105 aortic valves was collected from patients suffering from calcified aortic stenosis with either tricuspid valve (AS) or bicuspid aortic valve (BAV), rheumatic aortic stenosis (RA), endocarditis, or aortic regurgitation (AR). Each valve was incubated for 24 h in culture medium and the supernatants (conditioned media) were used to measure the concentrations of leukotriene B4 (LTB4) and TGF-beta1 and to quantify the number of MPs released. Valvular calcification was evaluated using biphotonic absorptiometry. RESULTS: LTB4 concentrations were significantly higher in media conditioned by AS valves compared to those conditioned by RA and endocarditis valves. In addition, LTB4 concentrations correlated significantly with the calcium content of the aortic valves. In contrast, the concentrations of TGF-beta1 and MPs in the conditioned media did not differ significantly between the various groups of valves, and there was no significant correlation between calcification and either TGF-beta1 or the number of MPs released from the aortic valves. CONCLUSION: Taken together, these results indicate that inflammatory signaling through LTB4 may be more closely linked to calcification and aortic stenosis than signaling through TGF-beta1 and MPs.