RESUMEN
OBJECTIVE: Several patients undergoing endovascular intervention and bypass surgery present with high platelet reactivity following clopidogrel treatment. We aimed to determine the frequency of the genetic polymorphism of CYP2C19*2 and the contribution of this polymorphism along with other clinical parameters to clopidogrel response in an Egyptian population. PATIENTS AND METHODS: A total of 50 patients receiving clopidogrel at a maintenance dose of 75 mg daily post vascular intervention from January 1, 2019, to May 30, 2020, were enrolled in this study. Clopidogrel resistance was determined through platelet aggregation analysis using Chrono-Log® platelet aggregometer. Single-nucleotide polymorphism (SNP) genotyping was performed using quantitative real-time polymerase chain reaction (QRT-PCR). RESULTS: The incidence of clopidogrel resistance among this Egyptian population is about 22%. Univariate analysis demonstrated that CYP2C19*2 genotype (p = 0.001), high body mass index (BMI; p = 0.025), diabetes (p = 0.037), high fasting blood glucose (FBG) level (p = 0.037), and high glycosylated hemoglobin (HbA1c) level (p = 0.004) were significantly associated with clopidogrel resistance. Multivariate analysis showed that CYP2C19*2 genotype (odds ratio (OR), 927.71; 95% confidence interval (CI), 1.915-449496.2; p = 0.030) and high BMI (OR, 1.789; 95% CI, 1.044-3.064; p = 0.034) were the most powerful predictors of clopidogrel resistance. CONCLUSIONS: Clopidogrel resistance in patients with peripheral vascular disease is associated with the presence of CYP2C19*2 allele, obesity, and diabetes; these factors should be considered prior to clopidogrel administration.
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Clopidogrel/farmacología , Citocromo P-450 CYP2C19/genética , Enfermedades Vasculares Periféricas/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/farmacología , Anciano , Alelos , Plaquetas/efectos de los fármacos , Estudios Transversales , Diabetes Mellitus/epidemiología , Resistencia a Medicamentos/genética , Egipto , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Obesidad/epidemiología , Enfermedades Vasculares Periféricas/genética , Agregación Plaquetaria/efectos de los fármacos , Polimorfismo de Nucleótido SimpleRESUMEN
(1) Aim: To investigate the causal effects of T2DM liability and glycated haemoglobin (HbA1c) levels on various cardiovascular disease outcomes, both in the general population and in non-diabetic individuals specifically. (2) Methods: We selected 243 variants as genetic instruments for T2DM liability and 536 variants for HbA1c. Linear Mendelian randomization analyses were performed to estimate the associations of genetically-predicted T2DM liability and HbA1c with 12 cardiovascular disease outcomes in 367,703 unrelated UK Biobank participants of European ancestries. We performed secondary analyses in participants without diabetes (HbA1c < 6.5% with no diagnosed diabetes), and in participants without diabetes or pre-diabetes (HbA1c < 5.7% with no diagnosed diabetes). (3) Results: Genetically-predicted T2DM liability was positively associated (p < 0.004, 0.05/12) with peripheral vascular disease, aortic valve stenosis, coronary artery disease, heart failure, ischaemic stroke, and any stroke. Genetically-predicted HbA1c was positively associated with coronary artery disease and any stroke. Mendelian randomization estimates generally shifted towards the null when excluding diabetic and pre-diabetic participants from analyses. (4) Conclusions: This genetic evidence supports causal effects of T2DM liability and HbA1c on a range of cardiovascular diseases, suggesting that improving glycaemic control could reduce cardiovascular risk in a general population, with greatest benefit in individuals with diabetes.
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Enfermedades Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Hemoglobina Glucada/genética , Estenosis de la Válvula Aórtica/complicaciones , Estenosis de la Válvula Aórtica/epidemiología , Estenosis de la Válvula Aórtica/genética , Estenosis de la Válvula Aórtica/patología , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/patología , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/patología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/patología , Femenino , Estudios de Asociación Genética , Variación Genética/genética , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Humanos , Accidente Cerebrovascular Isquémico/complicaciones , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/genética , Accidente Cerebrovascular Isquémico/patología , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Enfermedades Vasculares Periféricas/complicaciones , Enfermedades Vasculares Periféricas/epidemiología , Enfermedades Vasculares Periféricas/genética , Enfermedades Vasculares Periféricas/patología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/patologíaRESUMEN
Oncogenic RAS variants lead to constitutive overactivation and increased signal transduction into downstream pathways. They are found as somatic driver events in various types of human cancer. In a somatic mosaic status, the same RAS variants have been associated with a wide spectrum of focal or segmental tissue dysplasia and overgrowth including various types of congenital nevi, vascular malformations, and other changes (mosaic RASopathies). We present a 3-year-old male patient with segmental overgrowth of the subcutaneous fatty tissue of the right lower extremity with colocalized arteriovenous and capillary malformations and dysplastic draining veins in combination with talipes equinovarus of the right foot. In tissue biopsies of the affected extremity, we identified a mosaic KRAS variant, c.35G>A (p.Gly12Asp), while this variant was absent in the DNA extracted from a biopsy of the normal extremity. This report provides further evidence for the wide clinical and phenotypic variability associated with mosaic KRAS variants. The described pattern confirms that the combination of segmental overgrowth and vascular anomalies in the form of arteriovenous and capillary malformations is a possible manifestation of a mosaic RASopathy. The accurate genetic diagnosis is crucial for molecular-targeted therapy, which might be a future therapeutic target for mosaic RASopathies.
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Predisposición Genética a la Enfermedad , Enfermedades Vasculares Periféricas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Malformaciones Vasculares/genética , Preescolar , Humanos , Masculino , Mutación/genética , Enfermedades Vasculares Periféricas/diagnóstico , Enfermedades Vasculares Periféricas/patología , Fenotipo , Malformaciones Vasculares/diagnóstico , Malformaciones Vasculares/patologíaRESUMEN
Gain-of-function mutations in STING1 cause the monogenic interferonopathy, SAVI, which presents with early-onset systemic inflammation, cold-induced vasculopathy and/or interstitial lung disease. We identified 5 patients (3 kindreds) with predominantly peripheral vascular disease who harbor 3 novel STING1 variants, p.H72N, p.F153V, and p.G158A. The latter two were predicted by a previous cryo-EM structure model to cause STING autoactivation. The p.H72N variant in exon 3, however, is the first SAVI-causing variant in the transmembrane linker region. Mutations of p.H72 into either charged residues or hydrophobic residues all led to dramatic loss of cGAMP response, while amino acid changes to residues with polar side chains were able to maintain the wild type status. Structural modeling of these novel mutations suggests a reconciled model of STING activation, which indicates that STING dimers can oligomerize in both open and closed states which would obliviate a high-energy 180° rotation of the ligand-binding head for STING activation, thus refining existing models of STING activation. Quantitative comparison showed that an overall lower autoactivating potential of the disease-causing mutations was associated with less severe lung disease, more severe peripheral vascular disease and the absence of a robust interferon signature in whole blood. Our findings are important in understanding genotype-phenotype correlation, designing targeted STING inhibitors and in dissecting differentially activated pathways downstream of different STING mutations.
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Inflamación/genética , Enfermedades Pulmonares Intersticiales/genética , Proteínas de la Membrana/genética , Mutación , Enfermedades Vasculares Periféricas/genética , Adulto , Niño , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Células HEK293 , Humanos , Inflamación/diagnóstico , Inflamación/metabolismo , Inflamación/terapia , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/metabolismo , Enfermedades Pulmonares Intersticiales/terapia , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Modelos Moleculares , Enfermedades Vasculares Periféricas/diagnóstico , Enfermedades Vasculares Periféricas/metabolismo , Enfermedades Vasculares Periféricas/terapia , Fenotipo , Conformación Proteica , Multimerización de Proteína , Índice de Severidad de la Enfermedad , Relación Estructura-Actividad , Secuenciación del Exoma , Adulto JovenRESUMEN
Although coronavirus disease 2019 seems to be the leading topic in research number of outstanding studies have been published in the field of aorta and peripheral vascular diseases likely affecting our clinical practice in the near future. This review article highlights key research on vascular diseases published in 2020. Some studies have shed light in the pathophysiology of aortic aneurysm and dissection suggesting a potential role for kinase inhibitors as new therapeutic options. A first proteogenomic study on fibromuscular dysplasia (FMD) revealed a promising novel disease gene and provided proof-of-concept for a protein/lipid-based FMD blood test. The role of NADPH oxidases in vascular physiology, and particularly endothelial cell differentiation, is highlighted with potential for cell therapy development. Imaging of vulnerable plaque has been an intense field of research. Features of plaque vulnerability on magnetic resonance imaging as an under-recognized cause of stroke are discussed. Major clinical trials on lower extremity peripheral artery disease have shown added benefit of dual antithrombotic (aspirin plus rivaroxaban) treatment.
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Enfermedades de la Aorta , Investigación Biomédica/tendencias , Enfermedades Vasculares Periféricas , Animales , Enfermedades de la Aorta/diagnóstico , Enfermedades de la Aorta/epidemiología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/terapia , COVID-19 , Ensayos Clínicos como Asunto , Difusión de Innovaciones , Humanos , Enfermedades Vasculares Periféricas/diagnóstico , Enfermedades Vasculares Periféricas/epidemiología , Enfermedades Vasculares Periféricas/genética , Enfermedades Vasculares Periféricas/terapia , PronósticoRESUMEN
Importance: Smoking is associated with atherosclerotic cardiovascular disease, but the relative contribution to each subtype (coronary artery disease [CAD], peripheral artery disease [PAD], and large-artery stroke) remains less well understood. Objective: To determine the association between genetic liability to smoking and risk of CAD, PAD, and large-artery stroke. Design, Setting, and Participants: Mendelian randomization study using summary statistics from genome-wide associations of smoking (UK Biobank; up to 462â¯690 individuals), CAD (Coronary Artery Disease Genome Wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics Consortium; up to 60â¯801 cases, 123â¯504 controls), PAD (VA Million Veteran Program; up to 24â¯009 cases, 150â¯983 controls), and large-artery stroke (MEGASTROKE; up to 4373 cases, 406â¯111 controls). This study was conducted using summary statistic data from large, previously described cohorts. Review of those publications does not reveal the total recruitment dates for those cohorts. Data analyses were conducted from August 2019 to June 2020. Exposures: Genetic liability to smoking (as proxied by genetic variants associated with lifetime smoking index). Main Outcomes and Measures: Risk (odds ratios [ORs]) of CAD, PAD, and large-artery stroke. Results: Genetic liability to smoking was associated with increased risk of PAD (OR, 2.13; 95% CI, 1.78-2.56; P = 3.6 × 10-16), CAD (OR, 1.48; 95% CI, 1.25-1.75; P = 4.4 × 10-6), and stroke (OR, 1.40; 95% CI, 1.02-1.92; P = .04). Genetic liability to smoking was associated with greater risk of PAD than risk of large-artery stroke (ratio of ORs, 1.52; 95% CI, 1.05-2.19; P = .02) or CAD (ratio of ORs, 1.44; 95% CI, 1.12-1.84; P = .004). The association between genetic liability to smoking and atherosclerotic cardiovascular diseases remained independent from the effects of smoking on traditional cardiovascular risk factors. Conclusions and Relevance: In this mendelian randomization analysis of data from large studies of atherosclerotic cardiovascular diseases, genetic liability to smoking was a strong risk factor for CAD, PAD, and stroke, although the estimated association was strongest between smoking and PAD. The association between smoking and atherosclerotic cardiovascular disease was independent of traditional cardiovascular risk factors.
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Aterosclerosis/genética , Enfermedades Cardiovasculares/genética , Análisis de la Aleatorización Mendeliana , Fumar , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Enfermedades Vasculares Periféricas/genética , Factores de Riesgo , Accidente Cerebrovascular/genéticaRESUMEN
Thanks to a better knowledge of the genetic causes of many diseases and an improvement in genetic testing techniques, genetics has gained an important role in the multidisciplinary approach to diagnosis and management of congenital heart disease and aortic pathology. With the introduction of strategies for precision medicine, it is expected that this will only increase further in the future. Because basic knowledge of the indications, the opportunities as well as the limitations of genetic testing is essential for correct application in clinical practice, this consensus document aims to give guidance to care-providers involved in the follow-up of adults with congenital heart defects and/or with hereditary aortic disease. This paper is the result of a collaboration between the ESC Working Group of Grown-Up Congenital Heart Disease, the ESC Working Group on Aorta and Peripheral Vascular Disease and the European Society of Human Genetics. Throughout the document, the importance of correct counseling in the process of genetic testing is emphasized, indications and timing for genetic studies are discussed as well as the technical modalities of genetic testing. Finally, the most important genetic diseases in adult congenital heart disease and aortic pathology are also discussed.
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Enfermedades de la Aorta/genética , Cardiología , Consenso , Asesoramiento Genético/métodos , Pruebas Genéticas/métodos , Cardiopatías Congénitas/genética , Enfermedades Vasculares Periféricas/genética , Enfermedades de la Aorta/diagnóstico , Europa (Continente) , Cardiopatías Congénitas/diagnóstico , Humanos , Enfermedades Vasculares Periféricas/líquido cefalorraquídeo , Sociedades MédicasRESUMEN
BACKGROUND: Hyponatremia is a well-established poor prognostic marker in patients with heart failure. Whether the mortality risk is comparable among different races of patients with heart failure and hyponatremia is unknown. MATERIALS AND METHODS: Consecutive patients admitted with acute decompensated heart failure and an admission sodium level<135 mEq/L from 1/1/2001 through 12/31/10 were identified. Patients were divided into four groups based on self-reported race: white, African American, Hispanic and other. African Americans were used as the reference group for statistical analysis. The primary outcome was all-cause mortality. RESULTS: We included 4,343 patients, from which 1,356 (31%) identified as white, 1,248 (29%) as African American, 780 (18%) as Hispanic and 959 (22%) as other. During a median follow-up of 23 months, a total of 2,384 patients died: 678 were African American, 820 were white, 298 were Hispanic and 588 were other. After adjusting for baseline demographics, comorbidities and medication use, Hispanic patients had a 45% less risk of death as compared to African Americans (HR .55, CI .48-.64, p<0.05). There was no difference in mortality between white and African American patients (HR 1.04, CI .92-1.2, p = 0.79). CONCLUSION: Hispanic patients admitted for heart failure and who were hyponatremic on admission had an independent lower risk of mortality compared to other groups. These findings may be due to the disparate activity of the renin-angiotensin-aldosterone system among various racial groups. This observational study is hypothesis generating and suggests that treatment of patients with heart failure and hyponatremia should perhaps be focused more on renin-angiotensin-aldosterone system reduction in certain racial groups, yet less in others.
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Fibrilación Atrial/fisiopatología , Insuficiencia Cardíaca/mortalidad , Hiponatremia/mortalidad , Infarto del Miocardio/mortalidad , Negro o Afroamericano/genética , Anciano , Fibrilación Atrial/genética , Fibrilación Atrial/mortalidad , Comorbilidad , Femenino , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/fisiopatología , Hispánicos o Latinos/genética , Hospitalización , Humanos , Hiponatremia/genética , Hiponatremia/fisiopatología , Persona de Mediana Edad , Infarto del Miocardio/genética , Infarto del Miocardio/fisiopatología , Enfermedades Vasculares Periféricas/genética , Enfermedades Vasculares Periféricas/mortalidad , Enfermedades Vasculares Periféricas/fisiopatología , Estudios Retrospectivos , Factores de Riesgo , Población Blanca/genéticaRESUMEN
We report a 9-year-old girl homozygous for a loss-of-function mutation in the PIEZO-2 gene. She showed generalized muscular hypotonia with severe scoliosis, joint deformities, deficient proprioceptive function and selective atrophy and signal alterations of both gastrocnemii on whole body MRI scan. Light microscopic and ultrastructural examination showed few atrophic fibres, abnormal mitochondria, focal myofibrillar disruption and endomysial capillary microangiopathy.
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Canales Iónicos/genética , Hipotonía Muscular/genética , Músculo Esquelético/diagnóstico por imagen , Atrofia Muscular/genética , Mutación , Enfermedades Vasculares Periféricas/genética , Niño , Femenino , Humanos , Imagen por Resonancia Magnética , Hipotonía Muscular/diagnóstico por imagen , Atrofia Muscular/diagnóstico por imagen , Enfermedades Vasculares Periféricas/diagnóstico por imagenRESUMEN
BACKGROUND: Limb ischemia resulting from peripheral vascular disease is a common cause of morbidity. Vessel occlusion limits blood flow, creating a hypoxic environment that damages distal tissue, requiring therapeutic revascularization. Hypoxia-inducible factors (HIFs) are key transcriptional regulators of hypoxic vascular responses, including angiogenesis and arteriogenesis. Despite vascular smooth muscle cells' (VSMCs') importance in vessel integrity, little is known about their functional responses to hypoxia in peripheral vascular disease. This study investigated the role of VSMC HIF in mediating peripheral ischemic responses. METHODS AND RESULTS: We used ArntSMKO mice with smooth muscle-specific deletion of aryl hydrocarbon receptor nuclear translocator (ARNT, HIF-1ß), required for HIF transcriptional activity, in a femoral artery ligation model of peripheral vascular disease. ArntSMKO mice exhibit impaired perfusion recovery despite normal collateral vessel dilation and angiogenic capillary responses. Decreased blood flow manifests in extensive tissue damage and hypoxia in ligated limbs of ArntSMKO mice. Furthermore, loss of aryl hydrocarbon receptor nuclear translocator changes the proliferation, migration, and transcriptional profile of cultured VSMCs. ArntSMKO mice display disrupted VSMC morphologic features and wrapping around arterioles and increased vascular permeability linked to decreased local blood flow. CONCLUSIONS: Our data demonstrate that traditional vascular remodeling responses are insufficient to provide robust peripheral tissue reperfusion in ArntSMKO mice. In all, this study highlights HIF responses to hypoxia in arteriole VSMCs critical for the phenotypic and functional stability of vessels that aid in the recovery of blood flow in ischemic peripheral tissues.
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Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Regulación de la Expresión Génica , Isquemia/genética , Extremidad Inferior/irrigación sanguínea , Músculo Liso Vascular/metabolismo , Enfermedades Vasculares Periféricas/genética , Animales , Translocador Nuclear del Receptor de Aril Hidrocarburo/biosíntesis , Western Blotting , Células Cultivadas , Modelos Animales de Enfermedad , Inmunohistoquímica , Isquemia/metabolismo , Isquemia/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Músculo Liso Vascular/patología , Enfermedades Vasculares Periféricas/metabolismo , Enfermedades Vasculares Periféricas/patología , ARN/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The pathophysiology of sporadic Alzheimer's disease (AD) remains uncertain. Along with brain amyloid-ß (Aß) deposits and neurofibrillary tangles, cerebrovascular dysfunction is increasingly recognized as fundamental to the pathogenesis of AD. Using an experimental model of limb ischemia in transgenic APPPS1 mice, a model of AD (AD mice), we showed that microvascular impairment also extends to the peripheral vasculature in AD. At D70 following femoral ligation, we evidenced a significant decrease in cutaneous blood flow (- 29%, P < 0.001), collateral recruitment (- 24%, P < 0.001), capillary density (- 22%; P < 0.01) and arteriole density (- 28%; P < 0.05) in hind limbs of AD mice compared to control WT littermates. The reactivity of large arteries was not affected in AD mice, as confirmed by unaltered size, and vasoactive responses to pharmacological stimuli of the femoral artery. We identified blood as the only source of Aß in the hind limb; thus, circulating Aß is likely responsible for the impairment of peripheral vasculature repair mechanisms. The levels of the majority of pro-angiogenic mediators were not significantly modified in AD mice compared to WT mice, except for TGF-ß1 and PlGF-2, both of which are involved in vessel stabilization and decreased in AD mice (P = 0.025 and 0.019, respectively). Importantly, endothelin-1 levels were significantly increased, while those of nitric oxide were decreased in the hind limb of AD mice (P < 0.05). Our results suggest that vascular dysfunction is a systemic disorder in AD mice. Assessment of peripheral vascular function may therefore provide additional tools for early diagnosis and management of AD.
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Enfermedad de Alzheimer/fisiopatología , Miembro Posterior/fisiopatología , Isquemia/fisiopatología , Enfermedades Vasculares Periféricas/fisiopatología , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Arteriolas/metabolismo , Arteriolas/fisiopatología , Capilares/metabolismo , Capilares/fisiopatología , Modelos Animales de Enfermedad , Endotelina-1/sangre , Arteria Femoral/metabolismo , Arteria Femoral/fisiopatología , Miembro Posterior/irrigación sanguínea , Humanos , Isquemia/genética , Ratones , Ratones Transgénicos , Microcirculación/genética , Óxido Nítrico/sangre , Enfermedades Vasculares Periféricas/sangre , Enfermedades Vasculares Periféricas/genética , Factor de Crecimiento Placentario/sangre , Factor de Crecimiento Transformador beta1/sangreRESUMEN
The liver is vital for xenobiotic and endobiotic metabolism. Previously, we demonstrated that a compromised liver worsened toxicity associated with exposure to polychlorinated biphenyls (PCBs), through disruption of energy homeostasis. However, the role of a compromised liver in defining dioxin-like PCB126 toxicity on the peripheral vasculature and associated inflammatory diseases is yet to be studied. This study investigated the effects of PCB126 on vascular inflammation linked to hepatic dysfunction utilizing a liver injury mouse model. Male C57Bl/6 mice were fed either an amino acid control diet (CD) or a methionine-choline deficient (MCD) diet in this 14-week study. Mice were exposed to PCB126 (0.5 mg/kg) and analyzed for inflammatory, calorimetric and metabolic parameters. MCD diet-fed mice demonstrated steatosis, indicative of a compromised liver. Mice fed the MCD-diet and subsequently exposed to PCB126 manifested lower body fat mass, increased liver to body weight ratio and alterations in hepatic gene expression related to lipid and carbohydrate metabolism, implicating metabolic disturbances. PCB126-induced steatosis irrespective of the diet type, but only the MCD + PCB126 group exhibited steatohepatitis and fibrosis. Furthermore, PCB126 exposure in MCD-fed mice led to increased plasma inflammatory markers such as Icam-1, plasminogen activator inhibitor-1 and proatherogenic trimethylamine-N-oxide, suggesting inflammation of the peripheral vasculature that is characteristic of atherosclerosis. Taken together, our data provide new evidence of a link between a compromised liver, PCB-mediated hepatic inflammation and vascular inflammatory markers, suggesting that environmental pollutants can promote crosstalk between different organ systems, leading to inflammatory disease pathologies.
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Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Contaminantes Ambientales/toxicidad , Cirrosis Hepática/inducido químicamente , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedades Vasculares Periféricas/inducido químicamente , Bifenilos Policlorados/toxicidad , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Deficiencia de Colina , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Contaminantes Ambientales/metabolismo , Regulación de la Expresión Génica , Mediadores de Inflamación/metabolismo , Hígado/patología , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Masculino , Metionina/deficiencia , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedades Vasculares Periféricas/genética , Enfermedades Vasculares Periféricas/metabolismo , Bifenilos Policlorados/metabolismoRESUMEN
BACKGROUND: There is keen interest in finding nonsurgical treatments for peripheral vascular disease (PVD). Previously, we demonstrated that selective activation of Thioredoxin1 (Trx1), a 12-kDa cytosolic protein, initiates redox-dependent signaling and promotes neovascularization after ischemic heart disease. Therefore, Trx1 might possess immense potential to not only treat murine hind limb ischemia (HLI) through effective angiogenesis but also provide PVD patients with nonsurgical therapy to enhance neovascularization and improve blood perfusion. METHODS: To determine whether activation of Trx1 increases blood perfusion in HLI, two different strategies were used-gene therapy and transgenic model system. In adenoviral-mediated gene therapy, 8- to 12-wk-old mice were divided into two groups: (1) control Adeno-LacZ (Ad-LacZ) and (2) Adeno-Thiroedoxin1 (Ad-Trx1). The mice underwent surgical intervention to induce right HLI followed by injection with Ad-LacZ or Ad-Trx1, respectively. In the second strategy, we used wild-type and transgenic mice overexpressing Trx1 (Trx1Tg/+). All the animals underwent Doppler imaging for the assessment of limb perfusion followed by immunohistochemistry and Western blot analysis. RESULTS: Significant increases in perfusion ratio were observed in all the Trx1 overexpressed groups compared with their corresponding controls. Expressions of heme oxygenase-1, vascular endothelial growth factor, and the vascular endothelial growth factor receptors Flk-1 and Flt-1 were increased in Trx1 overexpressed mice compared with their respective controls. Blood perfusion in the ischemic limb gradually improved and significantly recovered in Trx1Tg/+ and Ad-Trx1 groups compared with their corresponding controls. The capillary and arteriolar density in the ischemic zone were found to be higher in Trx1Tg/+ group compared with wild type. CONCLUSIONS: The overall outcomes of our study demonstrate that Trx1 enhances blood perfusion and increases angiogenic protein expression in a rodent HLI model. These results suggest that Trx1 is a potential target for clinical trials and drug therapy for the treatment of PVD.
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Terapia Genética/métodos , Miembro Posterior/irrigación sanguínea , Isquemia/terapia , Enfermedades Vasculares Periféricas/terapia , Tiorredoxinas/metabolismo , Animales , Biomarcadores/metabolismo , Western Blotting , Miembro Posterior/metabolismo , Inmunohistoquímica , Isquemia/genética , Isquemia/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Enfermedades Vasculares Periféricas/genética , Enfermedades Vasculares Periféricas/metabolismo , Tiorredoxinas/genética , Regulación hacia ArribaRESUMEN
BACKGROUND: Alternative splicing mediated by RNA-binding proteins (RBPs) is emerging as a fundamental mechanism for the regulation of gene expression. Alternative splicing has been shown to be a widespread phenomenon that facilitates the diversification of gene products in a tissue-specific manner. Although defects in alternative splicing are rooted in many neurological disorders, only a small fraction of splicing factors have been investigated in detail. RESULTS: We find that the splicing factor Caper is required for the development of multiple different mechanosensory neuron subtypes at multiple life stages in Drosophila melanogaster. Disruption of Caper function causes defects in dendrite morphogenesis of larval dendrite arborization neurons and neuronal positioning of embryonic proprioceptors, as well as the development and maintenance of adult mechanosensory bristles. Additionally, we find that Caper dysfunction results in aberrant locomotor behavior in adult flies. Transcriptome-wide analyses further support a role for Caper in alternative isoform regulation of genes that function in neurogenesis. CONCLUSIONS: Our results provide the first evidence for a fundamental and broad requirement for the highly conserved splicing factor Caper in the development and maintenance of the nervous system and provide a framework for future studies on the detailed mechanism of Caper-mediated RNA regulation. Developmental Dynamics 246:610-624, 2017. © 2017 Wiley Periodicals, Inc.
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Drosophila melanogaster/citología , Drosophila melanogaster/metabolismo , Enfermedades Vasculares Periféricas/metabolismo , Proteínas de Unión al ARN/metabolismo , Células Receptoras Sensoriales/citología , Células Receptoras Sensoriales/metabolismo , Animales , Embrión de Pollo , Regulación del Desarrollo de la Expresión Génica/genética , Regulación del Desarrollo de la Expresión Génica/fisiología , Hemodinámica/genética , Hemodinámica/fisiología , Metamorfosis Biológica/genética , Metamorfosis Biológica/fisiología , Enfermedades Vasculares Periféricas/genética , Proteínas de Unión al ARN/genética , Piel/citología , Piel/metabolismoRESUMEN
Diabetes is strongly associated with systemic inflammation and oxidative stress, but its effect on pulmonary vascular disease and lung function has often been disregarded. Several studies identified restrictive lung disease and fibrotic changes in diabetic patients and in animal models of diabetes. While microvascular dysfunction is a well-known complication of diabetes, the mechanisms leading to diabetes-induced lung injury have largely been disregarded. We described the potential involvement of diabetes-induced platelet-endothelial interactions in perpetuating vascular inflammation and oxidative injury leading to fibrotic changes in the lung. Changes in nitric oxide synthase (NOS) activation and decreased NO bioavailability in the diabetic lung increase platelet activation and vascular injury and may account for platelet hyperreactivity reported in diabetic patients. Additionally, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway has been reported to mediate pancreatic islet damage, and is implicated in the onset of diabetes, inflammation and vascular injury. Many growth factors and diabetes-induced agonists act via the JAK/STAT pathway. Other studies reported the contribution of the JAK/STAT pathway to the regulation of the pulmonary fibrotic process but the role of this pathway in the development of diabetic lung fibrosis has not been considered. These observations may open new therapeutic perspectives for modulating multiple pathways to mitigate diabetes onset or its pulmonary consequences.
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Plaquetas/patología , Diabetes Mellitus/patología , Células Endoteliales/patología , Pulmón/patología , Enfermedades Vasculares Periféricas/patología , Fibrosis Pulmonar/patología , Animales , Plaquetas/metabolismo , Comunicación Celular , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Células Endoteliales/metabolismo , Regulación de la Expresión Génica , Humanos , Inflamación , Janus Quinasa 1/genética , Janus Quinasa 1/metabolismo , Pulmón/irrigación sanguínea , Pulmón/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo , Enfermedades Vasculares Periféricas/genética , Enfermedades Vasculares Periféricas/metabolismo , Activación Plaquetaria , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/metabolismo , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Hepatic venous outflow tract obstruction (HVOTO) and extrahepatic portal venous obstruction (EHPVO) are important causes of portal hypertension and related complications in India. Both these conditions result from splanchnic venous thrombosis. In recent years, a V617F somatic mutation in Janus kinase 2 (JAK2) gene which is highly specific for myeloproliferative disorders has been detected in 40 % to 50 % and 30 % to 35 % of Western patients with HVOTO and EHPVO, respectively. However, data on this mutation in these conditions from Asian countries are limited. METHODS: We looked for JAK2 V617F mutation in Indian patients with HVOTO (n = 40, median age 31 [range 17-51] years, 21 female) and EHPVO (n = 50, median age 23 [15-70] years, 25 female) by using two separate methods. Both the methods involved polymerase chain reaction using allele-specific primers. Positive results on one or both of these techniques were confirmed using DNA sequencing. RESULTS: None of the 40 patients with HVOTO and only 1 of 50 patients with EHPVO was found to have JAK2 V617F mutation. In the one patient who was found to have this mutation, both the PCR methods and DNA sequencing showed positive results. CONCLUSION: Hypercoagulability associated with JAK2 V617F mutation and associated chronic myeloproliferative disorders was not a major cause of HVOTO and EHPVO in this population.
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Síndrome de Budd-Chiari/genética , Estudios de Asociación Genética , Janus Quinasa 2/genética , Mutación , Enfermedades Vasculares Periféricas/genética , Vena Porta , Adolescente , Adulto , Anciano , Síndrome de Budd-Chiari/etiología , Enfermedad Crónica , Femenino , Humanos , Hipertensión Portal/etiología , India , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos , Enfermedades Vasculares Periféricas/etiología , Trombosis de la Vena/complicaciones , Adulto JovenRESUMEN
Cardiovascular disease (CD) and peripheral vascular disease (PVD) are leading causes of mortality and morbidity in western countries and also responsible of a huge burden in terms of disability, functional decline, and healthcare costs. Biomarkers are measurable biological elements that reflect particular physiological or pathological states or predisposition towards diseases and they are currently widely studied in medicine and especially in CD. In this context, biomarkers can also be used to assess the severity or the evolution of several diseases, as well as the effectiveness of particular therapies. Genomics, transcriptomics, and proteomics have opened new windows on disease phenomena and may permit in the next future an effective development of novel diagnostic and prognostic medicine in order to better prevent or treat CD. This review will consider the current evidence of novel biomarkers with clear implications in the improvement of risk assessment, prevention strategies, and medical decision making in the field of CD.
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Biomarcadores/análisis , Enfermedades Cardiovasculares , Perfilación de la Expresión Génica , Marcadores Genéticos/genética , Genómica , Enfermedades Vasculares Periféricas , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Humanos , Enfermedades Vasculares Periféricas/genética , Enfermedades Vasculares Periféricas/metabolismoRESUMEN
Peripheral vascular disease (PVD) is one of the most prevalent vascular diseases in the U.S. afflicting an estimated 8 million people. Obstruction of peripheral arteries leads to insufficient nutrients and oxygen supply to extremities, which, if not treated properly, can potentially give rise to a severe condition called critical limb ischemia (CLI). CLI is associated with extremely high morbidities and mortalities. Conventional treatments such as angioplasty, atherectomy, stent implantation and bypass surgery have achieved some success in treating localized macrovascular disease but are limited by their invasiveness. An emerging alternative is the use of growth factor (delivered as genes or proteins) and cell therapy for PVD treatment. By delivering growth factors or cells to the ischemic tissue, one can stimulate the regeneration of functional vasculature network locally, re-perfuse the ischemic tissue, and thus salvage the limb. Here we review recent advance in nanomaterials, and discuss how their application can improve and facilitate growth factor or cell therapies. Specifically, nanoparticles (NPs) can serve as drug carrier and target to ischemic tissues and achieve localized and sustained release of pro-angiogenic proteins. As nonviral vectors, NPs can greatly enhance the transfection of target cells with pro-angiogenic genes with relatively fewer safety concern. Further, NPs may also be used in combination with cell therapy to enhance cell retention, cell survival and secretion of angiogenic factors. Lastly, nano/micro fibrous vascular grafts can be engineered to better mimic the structure and composition of native vessels, and hopefully overcome many complications/limitations associated with conventional synthetic grafts.
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Extremidades/irrigación sanguínea , Isquemia/terapia , Nanomedicina/métodos , Enfermedades Vasculares Periféricas/terapia , Animales , Tratamiento Basado en Trasplante de Células y Tejidos , Humanos , Isquemia/genética , Isquemia/patología , Enfermedades Vasculares Periféricas/genética , Enfermedades Vasculares Periféricas/patología , Ingeniería de TejidosRESUMEN
OBJECTIVE: Urokinase-type plasminogen activator receptor (uPAR) is a key component of the fibrinolytic system involved in extracellular matrix remodelling and angiogenesis. The cleavage/inactivation of uPAR is a crucial step in fibroblast-to-myofibroblast transition and has been implicated in systemic sclerosis (SSc) microvasculopathy. In the present study, we investigated whether uPAR gene inactivation in mice could result in tissue fibrosis and peripheral microvasculopathy resembling human SSc. METHODS: The expression of the native full-length form of uPAR in human skin biopsies was determined by immunohistochemistry. Skin and lung sections from uPAR-deficient (uPAR(-/-)) and wild-type (uPAR(+/+)) mice at 12 and 24â weeks of age were stained with haematoxylin-eosin, Masson's trichrome and Picrosirius red. Dermal thickness and hydroxyproline content in skin and lungs were quantified. Dermal myofibroblast and microvessel counts were determined by immunohistochemistry for α-smooth muscle actin and CD31, respectively. Endothelial cell apoptosis was assessed by TUNEL/CD31 immunofluorescence assay. RESULTS: Full-length uPAR expression was significantly downregulated in SSc dermis, especially in fibroblasts and endothelial cells. Dermal thickness, collagen content and myofibroblast counts were significantly greater in uPAR(-/-) than in uPAR(+/+) mice. In uPAR(-/-) mice, dermal fibrosis was paralleled by endothelial cell apoptosis and severe loss of microvessels. Lungs from uPAR(-/-) mice displayed non-specific interstitial pneumonia-like pathological features, both with inflammation and collagen deposition. Pulmonary pathology worsened significantly from 12 to 24â weeks, as shown by a significant increase in alveolar septal width and collagen content. CONCLUSIONS: uPAR(-/-) mice are a new animal model closely mimicking the histopathological features of SSc. This model warrants future studies.
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Modelos Animales de Enfermedad , Fibrosis Pulmonar/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Esclerodermia Sistémica/genética , Piel/patología , Adulto , Anciano , Animales , Apoptosis , Biopsia , Colágeno/metabolismo , Citocinas/metabolismo , Progresión de la Enfermedad , Endotelio Vascular/patología , Femenino , Fibrosis , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microvasos/patología , Persona de Mediana Edad , Miofibroblastos/patología , Enfermedades Vasculares Periféricas/genética , Enfermedades Vasculares Periféricas/metabolismo , Enfermedades Vasculares Periféricas/patología , Receptores del Activador de Plasminógeno Tipo Uroquinasa/deficiencia , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/patología , Piel/irrigación sanguínea , Piel/metabolismoRESUMEN
Multiple genetic studies have suggested that high-temperature requirement serine protease (HTRA1) is associated with polypoidal choroidal vasculopathy (PCV). To date, no functional studies have investigated the biological effect of HTRA1 on vascular endothelial cells, essential vascular components involved in polypoidal vascular abnormalities and arteriosclerosis-like changes. In vitro studies were performed to investigate the effect of HTRA1 on the regulation of fibronectin, laminin, vascular endothelial growth factor (VEGF), platelet derived growth factor receptor (PDGFR) and matrix metalloparoteinases 2 (MMP-2) and the role of HTRA1 in choroid-retina endothelial (RF/6A) and human umbilical vein endothelial (HUVEC) cells. Lentivirus-mediated overexpression of HTRA1 was used to explore effects of the protease on RF/6A and HUVEC cells in vitro. HTRA1 overexpression inhibited the proliferation, cell cycle, migration and tube formation of RF/6A and HUVEC cells, effects that might contribute to the early stage of PCV pathological lesions. Fibronectin mRNA and protein levels were significantly down-regulated following the upregulation of HTRA1, whereas the expressions of laminin, VEGF and MMP-2 were unaffected by alterations in HTRA1 expression. The decreased biological function of vascular endothelial cells and the degradation of extracellular matrix proteins, such as fibronectin, may be involved in a contributory role for HTRA1 in PCV pathogenesis.