RESUMO
Aircraft noise induces vascular and cerebral inflammation and oxidative stress causing hypertension and cardiovascular/cerebral dysfunction. With the present studies, we sought to determine the role of myeloid cells in the vascular vs. cerebral consequences of exposure to aircraft noise. Toxin-mediated ablation of lysozyme M+ (LysM+) myeloid cells was performed in LysMCreiDTR mice carrying a cre-inducible diphtheria toxin receptor. In the last 4d of toxin treatment, the animals were exposed to noise at maximum and mean sound pressure levels of 85 and 72 dB(A), respectively. Flow cytometry analysis revealed accumulation of CD45+, CD11b+, F4/80+, and Ly6G-Ly6C+ cells in the aortas of noise-exposed mice, which was prevented by LysM+ cell ablation in the periphery, whereas brain infiltrates were even exacerbated upon ablation. Aircraft noise-induced increases in blood pressure and endothelial dysfunction of the aorta and retinal/mesenteric arterioles were almost completely normalized by ablation. Correspondingly, reactive oxygen species in the aorta, heart, and retinal/mesenteric vessels were attenuated in ablated noise-exposed mice, while microglial activation and abundance in the brain was greatly increased. Expression of phagocytic NADPH oxidase (NOX-2) and vascular cell adhesion molecule-1 (VCAM-1) mRNA in the aorta was reduced, while NFκB signaling appeared to be activated in the brain upon ablation. In sum, we show dissociation of cerebral and peripheral inflammatory reactions in response to aircraft noise after LysM+ cell ablation, wherein peripheral myeloid inflammatory cells represent a dominant part of the pathomechanism for noise stress-induced cardiovascular effects and their central nervous counterparts, microglia, as key mediators in stress responses.
Assuntos
Artérias/enzimologia , Encéfalo/enzimologia , Encefalite/prevenção & controle , Microglia/enzimologia , Muramidase/deficiência , Células Mieloides/enzimologia , Ruído dos Transportes/efeitos adversos , Doenças Vasculares Periféricas/prevenção & controle , Aeronaves , Animais , Artérias/fisiopatologia , Encéfalo/patologia , Modelos Animais de Doenças , Encefalite/enzimologia , Encefalite/etiologia , Encefalite/patologia , Deleção de Genes , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/patologia , Muramidase/genética , Estresse Oxidativo , Doenças Vasculares Periféricas/enzimologia , Doenças Vasculares Periféricas/etiologia , Doenças Vasculares Periféricas/fisiopatologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
The systemic and cerebral microcirculation contribute critically to regulation of local and global blood flow and perfusion pressure. Microvascular dysfunction, commonly seen in numerous cardiovascular pathologies, is associated with alterations in the oxidative environment including potentiated production of reactive oxygen species (ROS) and subsequent activation of redox signaling pathways. NADPH oxidases (Noxs) are a primary source of ROS in the vascular system and play a central role in cardiovascular health and disease. In this review, we focus on the roles of Noxs in ROS generation in resistance arterioles and capillaries, and summarize their contributions to microvascular physiology and pathophysiology in both systemic and cerebral microcirculation. In light of the accumulating evidence that Noxs are pivotal players in vascular dysfunction of resistance arterioles, selectively targeting Nox isozymes could emerge as a novel and effective therapeutic strategy for preventing and treating microvascular diseases.
Assuntos
Envelhecimento/metabolismo , Microvasos/enzimologia , NADPH Oxidases/metabolismo , Doenças Vasculares Periféricas/enzimologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Vasculite/enzimologia , Animais , Inibidores Enzimáticos/uso terapêutico , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Microcirculação/efeitos dos fármacos , Microvasos/efeitos dos fármacos , Microvasos/patologia , NADPH Oxidases/antagonistas & inibidores , Oxirredução , Estresse Oxidativo , Doenças Vasculares Periféricas/tratamento farmacológico , Doenças Vasculares Periféricas/patologia , Espécies Reativas de Oxigênio/metabolismo , Resistência Vascular/efeitos dos fármacos , Vasculite/tratamento farmacológico , Vasculite/patologiaRESUMO
Vascular calcification is an active cell-mediated process that reduces elasticity of blood vessels and increases blood pressure. Until now, the molecular basis of vascular calcification has not been fully understood. We previously reported that microtubule disturbances mediate vascular calcification. Here, we found that protein kinase C (PKC) signaling acted as a novel coordinator between cytoskeletal changes and hyperphosphatemia-induced vascular calcification. Phosphorylation and expression of both PKCα and PKCδ decreased during inorganic phosphate (Pi)-induced vascular smooth muscle cell (VSMC) calcification. Knockdown of PKC isoforms by short interfering RNA as well as PKC inactivation by Go6976 or rottlerin treatment revealed that specific inhibition of PKCα and PKCδ accelerated Pi-induced calcification both in VSMCs and ex vivo aorta culture through upregulation of osteogenic signaling. Additionally, inhibition of PKCα and PKCδ induced disassembly of microtubule and actin, respectively. In summary, our results indicate that cytoskeleton perturbation via PKCα and PKCδ inactivation potentiates vascular calcification through osteogenic signal induction.
Assuntos
Aorta/enzimologia , Calcinose/enzimologia , Citoesqueleto/metabolismo , Osteogênese , Doenças Vasculares Periféricas/enzimologia , Proteína Quinase C/metabolismo , Animais , Aorta/patologia , Calcinose/patologia , Células Cultivadas , Citoesqueleto/patologia , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Proteína Quinase C-delta/metabolismoRESUMO
BACKGROUND: Recent evidence suggests that Rho-kinase (ROCK) plays an important role in the pathogenesis of atherosclerosis and a marker of atherosclerotic burden. Polyvascular disease with concomitant peripheral arterial disease (PAD) and coronary artery disease (CAD) is common and associated with a worse prognosis. The aim of this study was to evaluate ROCK activity as a marker of polyvascular disease. METHODS: We retrospectively analyzed patients undergoing coronary angiography at our institution between February 2009 and May 2009. Patients with only CAD (n = 40) defined by coronary artery stenosis of ≥50% by angiography, only PAD (n = 40) defined by an ankle brachial index (ABI) <0.9, and combined CAD/PAD (n = 40) were matched by age and sex to control patients (n = 40) without CAD or PAD. ROCK activity was determined by phosphorylation of the myosin binding subunit in leukocytes and then compared between each group. Multivariate analysis was used to determine independent predictors of polyvascular disease. Discriminative ability of elevated ROCK activity was assessed using receiver operator characteristics (ROC) curves. RESULTS: Patients (age 68 ± 12 years, 79% male) with CAD, PAD, and CAD/PAD had a mean ABI of 1.08, 0.62, and 0.65, respectively, compared to 1.08 in the control group. There was an incremental increase in ROCK activity in patients with CAD (4.61 ± 2.11), PAD (4.27 ± 1.39), and CAD/PAD (5.96 ± 1.94) compared to control (2.40 ± 0.43) (all P < 0.05). ROCK activity (odds ratio: 4.53, 95% confidence interval: 1.26-6.30) was an independent predictor of polyvascular disease. The ROCK cutoff value of 4.85 had a sensitivity of 72.7% and a specificity of 65.7%, with an area under ROC curve of 0.71 for polyvascular disease. CONCLUSIONS: Patients with concomitant peripheral and coronary arterial disease are associated with increased Rho-kinase activity. Rho-kinase activity may be a potential marker of atherosclerotic burden for patients with polyvascular disease.
Assuntos
Doença da Artéria Coronariana/enzimologia , Inflamação/enzimologia , Doenças Vasculares Periféricas/enzimologia , Quinases Associadas a rho/metabolismo , Idoso , Idoso de 80 Anos ou mais , Índice Tornozelo-Braço , Área Sob a Curva , Biomarcadores/metabolismo , Angiografia Coronária , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Feminino , Humanos , Inflamação/complicações , Inflamação/diagnóstico , Leucócitos/enzimologia , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Doenças Vasculares Periféricas/complicações , Doenças Vasculares Periféricas/diagnóstico , Fosforilação , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de Doença , Regulação para CimaRESUMO
Matrix metalloproteinases are responsible for degradation and remodelling of extracellular matrix and exert important roles in initiation and progression of inflammatory diseases. We aimed to examine the role of Matrix metalloproteinases (MMPs) and their regulators in degenerative arterial diseases. Serum samples were collected from patients with arterial disease (n = 126), who underwent surgery because of symptomatic aorto-occlusive disease (AOD, n = 18), carotid artery stenosis (n = 67) or abdominal arotic aneurysm (n = 41). Serum MMP-1, MMP-8, MMP-13, TIMP-1, myeloperoxidase (MPO) and neutrophil elastase (HNE) concentrations were determined by ELISA, and the molar ratio of MMP-8 and TIMP-1 was calculated. To get reference values, the determinations were done on samples of healthy blood donors (n = 100). In univariate analyses, the patients had higher MMP-8 (P < 0.001), TIMP-1 (P = 0.045), and MMP-8/TIMP-1 (P < 0.001), and lower MPO (P < 0.001) when compared with the blood donors. All three subgroups had higher MMP-8 (P < 0.001) and MMP-8/TIMP-1 (P < 0.001), and lower MPO (P < 0.01, except AOD) levels when compared with the references. In multiple logistic regression analyses, the male gender (P < 0.01), age (P < 0.001), elevated MMP-8 (P < 0.001) and decreased MPO (P < 0.001) concentrations associated significantly with the risk for arterial disease, and provided an area under curve (AUC) of 0.97 in the Receiver operating characteristics analyses. In multiple linear regression analyses, HNE correlated with both MMP-8 (P < 0.001) and MPO (P = 0.008) concentrations. Combination of high MMP-8 and low MPO level in serum eventually reflecting selectively modified neutrophil degranulation may indicate increased risk for arterial disease.
Assuntos
Aneurisma da Aorta Abdominal/enzimologia , Metaloproteinase 8 da Matriz/sangue , Doenças Vasculares Periféricas/enzimologia , Peroxidase/sangue , Fatores Etários , Idoso , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/imunologia , Feminino , Humanos , Modelos Lineares , Masculino , Metaloproteinase 8 da Matriz/imunologia , Pessoa de Meia-Idade , Doenças Vasculares Periféricas/sangue , Doenças Vasculares Periféricas/imunologia , Peroxidase/imunologia , Curva ROC , Fatores Sexuais , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-1/imunologiaRESUMO
OBJECTIVE: Several biologic mediators and genetic predisposing factors may contribute to the development of peripheral arterial disease (PAD). The eNOS gene, encoding for endothelial nitric oxide synthase, has been proposed as a candidate gene in the predisposition to the disease. In this study, we evaluated the role of eNOS-786T>C, -894G>T and 4a/4b polymorphisms as markers of PAD per se and in the presence of the ACE D allele in patients previously investigated. METHODS: We analyzed 281 consecutive patients (220 men, 61 women; median age, 72 years) with PAD and 562 healthy controls, comparable for sex and age. RESULTS: eNOS-786C, but not -894T and 4a, allele frequency was significantly higher in PAD patients than in controls (P = .03). An association with the predisposition to PAD was found for the eNOS-786C allele (odds ratio [OR], 1.52; 95% confidence interval [CI], 1.11-2.09; P = .009) and the eNOS -786C/4a haplotype (OR, 1.41; 95% CI, 1.02-1.94, P = .04) at univariate analysis but not after adjustment for traditional risk factors. When smoking habit was considered, we observed that eNOS-786C/4a haplotype, but not the eNOS-786C allele, influenced PAD predisposition after adjustment for traditional risk factors in smokers (OR, 2.71; 95% CI, 1.38-5.30; P = .004). The eNOS-786C and eNOS-786C/4a haplotype did not modify the susceptibility to PAD in patients carrying the ACE D allele. Nevertheless, the presence of the eNOS-786C/4a haplotype increased PAD predisposition in smokers also carrying ACE D allele (OR, 2.71 to 3.79; P > .05 for interaction). CONCLUSIONS: This study demonstrated an association between eNOS and ACE genes in increasing PAD susceptibility in smokers, thus providing evidence for a gene-environment interaction in modulating predisposition to the disease.
Assuntos
Óxido Nítrico Sintase Tipo III/genética , Peptidil Dipeptidase A/genética , Doenças Vasculares Periféricas/etiologia , Fumar/efeitos adversos , Idoso , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Modelos Logísticos , Masculino , Razão de Chances , Doenças Vasculares Periféricas/enzimologia , Doenças Vasculares Periféricas/genética , Polimorfismo Genético , Estudos Retrospectivos , Medição de Risco , Fatores de RiscoRESUMO
Nitric oxide belongs to the most important factors influencing structural and functional properties of vessel wall. Both genetic and environmental factors may influence its metabolism. The aim of this study was to explore whether two common polymorphisms of endothelial nitric synthase (eNOS) may, jointly with smoking, influence the stiffness of large arteries, quantified as pulse wave velocity (PWV). One hundred ninety four subjects free of manifest atherosclerotic disease or chronic pharmacotherapy were selected from population-based postMONICA study. PWV´s were measured using Sphygmocor® device between carotic and femoral arteries (aortic PWV) and between femoral and tibialis-posterior arteries (peripheral PWV). Two common polymorphisms, T786C and G894T, were assessed. Among current smokers, homo- or heterozygous carriers of T786C mutation showed significantly higher peripheral PWV than normal genotype carriers (14.0 vs 10.7 m/s, p<0.002); the same was true for the carriers of G894T mutation (13.9 vs 11.0 m/s, p<0.015). No differences were found in non-smokers, and neither of the eNOS polymorphisms influenced aortic PWV in our setting. In conclusion, genetically determined disorder of nitric oxide metabolism was associated with increased stiffness of peripheral, muscular-type arteries in generally healthy, untreated subjects, but only in the interaction with current smoking.
Assuntos
Artérias/enzimologia , Pressão Sanguínea , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico/metabolismo , Doenças Vasculares Periféricas/genética , Polimorfismo Genético , Fumar/efeitos adversos , Artérias/fisiopatologia , Distribuição de Qui-Quadrado , Estudos Transversais , República Tcheca , Elasticidade , Feminino , Frequência do Gene , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Vasculares Periféricas/enzimologia , Doenças Vasculares Periféricas/fisiopatologia , Fenótipo , Medição de Risco , Fatores de RiscoRESUMO
OBJECTIVE: Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis. Apart from traditional cardiovascular risk factors, several novel biologic mediators and genetic predisposing factors appear relevant in determining the atherogenetic process leading to PAD. Genes encoding for renin angiotensin system (RAS) components have been proposed as candidate in atherosclerosis. This study investigated four polymorphisms in angiotensinogen (AGT), angiotensin converting enzyme (ACE), and angiotensin II receptor type 1 (AGTR1), genes of RAS, in both predicting PAD and modulating the severity of the disease. METHODS: The ACE I/D and -240A>T, AGT M235T, and AGTR1 1166A>C polymorphisms were analyzed in 281 PAD patients and in 485 controls comparable for age and sex. RESULTS: The ACE D and -240T alleles both significantly influenced the predisposition to PAD. The ACE D, but not -240 T, allele remained associated with PAD after Bonferroni correction (P = .004) and adjustment for cardiovascular risk factors (P = .03). The ACE D allele influenced PAD predisposition with a dose-dependent effect (odds ratio for ACE ID vs II genotype, 1.77; P = .006; ACE DD vs II genotype, 2.15; P = .001). The haplotype reconstruction analysis for the ACE gene showed that the D/-240T haplotype significantly and independently influenced the predisposition to PAD (P = .02). In 190 PAD patients with no additional atherosclerotic localizations (isolated PAD), a significant association between ACE D and -240T alleles and PAD was observed. Only the ACE D allele remained associated with isolated PAD after Bonferroni correction (P = .02) and after adjustment for cardiovascular risk factors (P = .02). The haplotype reconstruction analysis for the ACE gene showed that the D/-240T, but not the D/-240A haplotype significantly influenced the predisposition to PAD (P = .0003). No influence of the polymorphisms analyzed on the severity of the disease, according to Rutherford categories, was found. CONCLUSIONS: The present study contributes data to highlight the role of the ACED/-240T haplotype in predisposing to PAD, also in the absence of other atherosclerotic comorbidities.
Assuntos
Angiotensinogênio/genética , Peptidil Dipeptidase A/genética , Doenças Vasculares Periféricas/genética , Polimorfismo Genético , Receptor Tipo 1 de Angiotensina/genética , Sistema Renina-Angiotensina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Doenças Vasculares Periféricas/enzimologia , Fenótipo , Medição de Risco , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Myeloperoxidase (MPO) is an enzymatic mediator of several inflammatory cascades and higher serum levels have been associated with increased risk of adverse cardiovascular events. We investigated the association of serum MPO with the ankle-brachial index (ABI) and peripheral arterial disease (PAD) in a bi-ethnic cohort of African-Americans and non-Hispanic white individuals. Participants included 1324 African-Americans (mean age 64 years, 71% women) and 1237 non-Hispanic white individuals (mean age 59 years, 57% women) belonging to hypertensive sibships. Serum levels of MPO were measured by solid phase sandwich immunoassay. ABI was measured using a standard protocol and PAD was defined as an ABI < 0.90. Multivariable regression analysis using generalized estimating equations were performed to assess whether serum MPO levels were associated with ABI and the presence of PAD. After adjustment for age and sex, higher MPO levels were significantly associated with lower ABI and the presence of PAD in African-Americans (p = 0.004 and p = 0.005, respectively) and in non-Hispanic white individuals (p = 0.001 and p = 0.016, respectively). After additional adjustment for conventional risk factors (diabetes, smoking status, total and high-density lipoprotein cholesterol, waist circumference, hypertension), prior history of myocardial infarction or stroke, and medication use (statins, aspirin, estrogen), higher MPO levels remained significantly associated with lower ABI and the presence of PAD in both African-Americans (p = 0.008 and p = 0.010, respectively) and non-Hispanic white individuals (p = 0.001 and p = 0.018, respectively). We conclude that higher MPO levels are associated with lower ABI and the presence of PAD in African-Americans and non-Hispanic white individuals.
Assuntos
Tornozelo/irrigação sanguínea , Pressão Sanguínea , Artéria Braquial/fisiopatologia , Doenças Vasculares Periféricas/diagnóstico , Peroxidase/sangue , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Biomarcadores/sangue , Estudos Transversais , Regulação para Baixo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Vasculares Periféricas/enzimologia , Doenças Vasculares Periféricas/etnologia , Doenças Vasculares Periféricas/fisiopatologia , Valor Preditivo dos Testes , Curva ROC , Análise de Regressão , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia , População Branca/estatística & dados numéricosRESUMO
ADAMTS13 may play a role in arterial thrombosis by cleaving the highly active and thrombogenic ultralarge Von Willebrand Factor (VWF) multimers into less active VWF multimers. The aim was to investigate the relationship between plasma levels of ADAMTS13, VWF and genetic variation in the ADAMTS13 gene with cardiovascular disease. We performed a case-control study in 374 patients with a first-ever arterial thrombosis before the age of 45 years in males and 55 years in women. We included 218 patients with coronary heart disease (CHD), 109 patients with ischemic stroke (IS) and 47 patients with peripheral arterial disease (PAD) and 332 healthy population-based controls. ADAMTS13 and VWF levels were measured 1-3 months after the event. ADAMTS13 levels were associated with cardiovascular disease (OR antigen 5.1 (95% CI 3.1-8.5, p<0.001) and OR activity 4.4 (95% CI 2.5-7.5, p<0.001), in the lowest quartiles). VWF levels were associated with cardiovascular disease (OR antigen 2.1 (95% CI 1.3-3.3, p=0.001) and OR activity 2.0 (95% CI 1.3-3.1, p=0.003), in the highest quartile). Patients with combined low ADAMTS13 levels and high VWF levels had an odds ratio of 7.7 (95% CI 3.3-17.7) (p for trend <0.0001). No association was found between genetic variation in the ADAMTS13 gene with levels of ADAMTS13 or with risk of cardiovascular disease. In conclusion, levels of ADAMTS13 and VWF are strongly associated with the risk of cardiovascular disease.
Assuntos
Proteínas ADAM/sangue , Doenças Cardiovasculares/enzimologia , Proteínas ADAM/genética , Proteína ADAMTS13 , Adulto , Fatores Etários , Biomarcadores/sangue , Isquemia Encefálica/enzimologia , Doenças Cardiovasculares/genética , Estudos de Casos e Controles , Doença das Coronárias/enzimologia , Regulação para Baixo , Feminino , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Doenças Vasculares Periféricas/enzimologia , Fenótipo , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/enzimologia , Trombose/enzimologia , Fator de von Willebrand/metabolismoRESUMO
OBJECTIVE: Hyperhomocysteinaemia is associated with peripheral arterial disease (PAD). There are inter-individual variations in the metabolism of homocysteine because of genetic polymorphisms. This study analyzed the role of one polymorphism that is associated with raised homocysteine, as a risk factor for PAD. METHODS: This study considered the association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms with the incidence of PAD by performing a case-control study and a cross sectional study of homocysteine levels. We recruited 133 patients with PAD in Norfolk and compared the MTHFR allele distribution with 457 healthy individuals. We also carried out a meta-analysis to place our data within the context of other published studies. We searched Medline, Embase, and Cochrane databases up to March 2008 for any studies on the association between MTHFR C677T polymorphism and PAD. RESULTS: The MTHFR C677T allele frequencies in the cases and controls were 0.37 and 0.33, and the odds ratios for the association of the 677 T allele or TT genotype with PAD were 1.18 (95% Confidence Interval [CI] 0.89, 1.58) and 1.99 (95% CI 1.09, 3.63). Homozygotes for the MTHFR C677T mutation had higher concentrations of plasma total homocysteine, odds ratio 2.82 (95% CI 1.03, 7.77) compared to homozygotes for the MTHFR 677 CC genotype. Twelve of 72 articles retrieved from the database search reported the prevalence of mutations in PAD patients. A meta-analysis of 9 appropriate studies, including our own, showed that being homozygous for the C677T allele was associated with an increased risk of PAD, pooled odds ratio 1.36 (95% CI 1.09, 1.68). CONCLUSION: We have found a strong association between raised homocysteine, the TT genotype, and PAD.
Assuntos
Hiper-Homocisteinemia/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação , Doenças Vasculares Periféricas/genética , Polimorfismo Genético , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos Transversais , Inglaterra/epidemiologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Homocisteína/sangue , Homozigoto , Humanos , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/enzimologia , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Razão de Chances , Doenças Vasculares Periféricas/enzimologia , Fenótipo , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de RiscoRESUMO
High levels of thrombin-activatable fibrinolysis inhibitor (TAFI) are a supposed risk factor for thrombosis. However, results from previous studies are conflicting. We assessed the absolute risk of venous and arterial thromboembolism in subjects with high TAFI levels (>126 U/dl) versus subjects with normal levels, and the contribution of other concomitant thrombophilic defects. Relatives from four identical cohort studies in families with either deficiencies of antithrombin, protein C or protein S, prothrombin 20210A, high factor VIII levels, or hyperhomocysteinemia were pooled. Probands were excluded. Of 1,940 relatives, 187 had high TAFI levels. Annual incidences of venous thromboembolism were 0.23% in relatives with high TAFI levels versus 0.26% in relatives with normal TAFI levels (adjusted relative risk [RR] 0.8; 95% confidence interval [CI], 0.5-1.3). For arterial thrombosis these were 0.31% versus 0.23% (adjusted RR 1.4; 95% CI, 0.9-2.2). High levels of factor VIII, IX and XI were observed more frequently in relatives with high TAFI levels. Only high factor VIII levels were associated with an increased risk of venous and arterial thrombosis, independently of TAFI levels. None of these concomitant defects showed interaction with high TAFI levels. High TAFI levels were not associated with an increased risk of venous and arterial thromboembolism in thrombophilic families.
Assuntos
Carboxipeptidase B2/sangue , Doença da Artéria Coronariana/etiologia , Doenças Vasculares Periféricas/etiologia , Tromboembolia/etiologia , Trombofilia/complicações , Tromboembolia Venosa/etiologia , Adulto , Estudos de Coortes , Doença da Artéria Coronariana/enzimologia , Doença da Artéria Coronariana/epidemiologia , Fator IX/metabolismo , Fator VIII/metabolismo , Fator XI/metabolismo , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Doenças Vasculares Periféricas/enzimologia , Doenças Vasculares Periféricas/epidemiologia , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco , Tromboembolia/enzimologia , Tromboembolia/epidemiologia , Trombofilia/enzimologia , Trombofilia/epidemiologia , Regulação para Cima , Tromboembolia Venosa/enzimologia , Tromboembolia Venosa/epidemiologiaRESUMO
OBJECTIVE: The risk of cerebrovascular events in patients with mild to moderate peripheral vascular disease is significant. Cilostazol is a phosphodiesterase type 3 (PDE3) inhibitor that is effective in the treatment of symptoms of peripheral arterial occlusive disease. The method of action includes antithrombotic, vasodilatory, and antiproliferative effects. METHODS: The Cilostazol: A Study in Long-Term Effects (CASTLE) trial was a prospective randomized double-blinded trial to establish the safety of this PDE3 inhibitor use in 1435 patients with mild to moderate peripheral arterial occlusive disease. A post hoc analysis of the CASTLE trial was undertaken to evaluate cilostazol use on cerebrovascular events. Blinded adjudication of all cerebrovascular events (stroke, transient ischemic attack, and carotid revascularization) in this trial was performed. Kaplan-Meier analysis was used for statistical evaluation. RESULTS: The overall rate of cerebrovascular events was 4.6% (67 of 1435 patients) with a mean follow-up of 515 days. Ischemic vascular events were more common (2.5%) than hemorrhagic events (0.3%; P < .05). The placebo group demonstrated a greater risk for events (6.1%; 43 of 718 patients) versus the cilostazol treated group (3.2%; 24 of 717 patients; P < .05). Cerebrovascular risk factors were similar in both groups. CONCLUSION: The risk of cerebrovascular events in patients with mild to moderate peripheral arterial occlusive disease is 4.6% with a mean follow-up of 515 days. Treatment with PDE3 inhibitors may reduce this risk. Further evaluation of the use of PDE3 inhibitors for prevention of cerebrovascular events should be considered.
Assuntos
Fármacos Cardiovasculares/uso terapêutico , Transtornos Cerebrovasculares/prevenção & controle , Claudicação Intermitente/tratamento farmacológico , Doenças Vasculares Periféricas/tratamento farmacológico , Inibidores da Fosfodiesterase 3 , Inibidores de Fosfodiesterase/uso terapêutico , Tetrazóis/uso terapêutico , Idoso , Fármacos Cardiovasculares/farmacologia , Transtornos Cerebrovasculares/enzimologia , Transtornos Cerebrovasculares/etiologia , Cilostazol , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Método Duplo-Cego , Feminino , Humanos , Claudicação Intermitente/enzimologia , Claudicação Intermitente/etiologia , Masculino , Pessoa de Meia-Idade , Doenças Vasculares Periféricas/complicações , Doenças Vasculares Periféricas/enzimologia , Inibidores de Fosfodiesterase/farmacologia , Estudos Prospectivos , Medição de Risco , Índice de Gravidade de Doença , Tetrazóis/farmacologia , Fatores de Tempo , Resultado do TratamentoRESUMO
The K121Q variant of the ectonucleotide pyrophosphatase/ phosphodiesterase 1 (ENPP1) gene is associated with obesity, insulin resistance, and early myocardial infarction. Therefore, we hypothesized that the K121Q polymorphism might also be associated with an increased risk for peripheral arterial disease. Four hundred patients with peripheral arterial disease and 400 controls matched for sex and age (+/- 2 years) were genotyped cross-sectionally for the K121Q single nucleotide polymorphism of the ENPP1 gene. The frequency for the 121Q allele was 0.25 both in patients with peripheral arterial disease and in controls (P = 0.75). Subgroup analysis revealed association of the ENPP1 121QQ genotype with higher glycohemoglobin A1C levels (P = 0.001) and earlier onset of peripheral arterial disease (P = 0.003) in the cohort of nonsmokers. Whereas the K121Q genotype of the ENPP1 gene is not associated with presence of peripheral arterial disease in the whole Linz Peripheral Arterial Disease population, it is associated with type 2 diabetes mellitus and earlier onset of peripheral arterial disease in the subgroup of nonsmoking patients.
Assuntos
Doenças Vasculares Periféricas/genética , Diester Fosfórico Hidrolases/genética , Polimorfismo de Nucleotídeo Único , Pirofosfatases/genética , Idoso , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Vasculares Periféricas/enzimologia , Fatores de Risco , Fumar/efeitos adversosRESUMO
INTRODUCTION: Several pathological conditions can induce skeletal muscle atrophy and seem to share common enzyme pathways. In catabolic states where proteolysis is increased, two genes specific to muscle atrophy, MuRf1 and MAFbx, are upregulated. These encode ubiquitin ligases, which bind to and mediate ubiquitination of myofibrillar proteins for subsequent degradation during muscle atrophy. METHODS: Fifteen patients undergoing leg amputation were divided into two groups. Group A included 12 elderly patients (mean age 79years) amputated for vascular disease (complicated by diabetes in four), chronic osteomyelitis or squamous cell carcinoma. Group B included three car accident victims (mean age 32years) amputated due to acute arterial insufficiency. Gastrocnemius muscle biopsies were collected for a histochemical and immunohistochemical (anti-MuRf1, anti-MAFbx) study. RESULTS: Group A specimens showed a decreased cross-sectional fiber area and length, adipose tissue replacement, and MuRf1 and MAFbx immunoreactivity. Muscle cells showed MuRf1 and MAFbx subsarcolemmal immunoreactivity and weak extracellular matrix immunoreactivity. Group B samples exhibited mild muscle structural changes; they did not stain with anti-MuRf1 or anti-MAFbx, and neither did sections showing muscle degeneration and adipose tissue replacement. DISCUSSION: Results of our preliminary study showed upregulation of MuRf1 and MAFbx in atrophied muscle and support their role as regulatory peptides in various conditions that lead to muscle atrophy. Data suggest that the study of cellular pathways can help identify promising targets for effective new treatments for skeletal muscle atrophy. CONCLUSION: The treatment of several orthopedic conditions is complicated by muscle atrophy; potential treatments could be directed to specific sites where these proteins are localized.
Assuntos
Proteínas Musculares/metabolismo , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Proteínas Ligases SKP Culina F-Box/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica , Masculino , Osteomielite/enzimologia , Doenças Vasculares Periféricas/enzimologia , Sarcolema/enzimologia , Proteínas com Motivo Tripartido , Regulação para Cima/fisiologiaRESUMO
BACKGROUND: Paraoxonase-1 (PON1) is an antioxidative enzyme associated with HDL and its serum activity is associated with risk of cardiovascular disease. The interindividual variation in PON1 activity is partly determined by genetic factors, such as polymorphisms in the PON1 gene, but also by dietary factors like the antioxidants. AIM OF THE STUDY: We examined the effect of antioxidant-rich orange and blackcurrant juices and vitamin E supplement on PON1 activity in patients with peripheral arterial disease. Furthermore, we studied whether genetic polymorphisms in the PON1 gene predicted the change in PON1 activity. METHODS: The study was designed as a cross-over trial with 48 participants who received two of the four possible treatments: (1) 250 ml orange juice and 250 ml blackcurrant juice; (2) 15 mg vitamin E; (3) 250 ml orange juice and 250 ml blackcurrant juice and 15 mg vitamin E; or (4) control/placebo (energy-equivalent sugar-containing beverage). The treatments were given for 28 days, separated by a 4-week wash-out period. RESULTS: The PON1 activity was not affected by juice or vitamin E supplement neither was there evidence of synergetic effects. However, a statistically significant interaction was observed between treatment and PON1 genotype, such that PON1 activity increased after juice alone in patients carrying the PON1 L55-allele. Results need to be interpreted with care since the study population was relatively small. CONCLUSION: Consumption of orange and blackcurrant juice and vitamin E supplement does not affect the activity of PON1 in patients with peripheral arterial disease. However, a gene-diet interaction may be present.
Assuntos
Antioxidantes/farmacologia , Arildialquilfosfatase/metabolismo , Bebidas , Frutas/química , Doenças Vasculares Periféricas/enzimologia , Vitamina E/administração & dosagem , Adulto , Idoso , Arildialquilfosfatase/efeitos dos fármacos , Arildialquilfosfatase/genética , Citrus sinensis/química , Estudos Cross-Over , Suplementos Nutricionais , Feminino , Genótipo , Humanos , Lipoproteínas HDL/sangue , Masculino , Pessoa de Meia-Idade , Oxirredução , Doenças Vasculares Periféricas/tratamento farmacológico , Polimorfismo GenéticoRESUMO
Peripheral vascular disease is an atherosclerotic process. It has been suggested that angiotensin converting enzyme insertion/deletion polymorphism is associated with atherosclerosis. The aim of this study was to investigate the role of the insertion/deletion polymorphism of the angiotensin-converting enzyme in Turkish patients with peripheral vascular disease in Western part of Turkey. We also investigated the relationship between serum angiotensin converting enzyme activity and distribution of genotypes in both patients and control group. The study group consisted of 78 patients with peripheral vascular disease. The control group consisted of 73 healthy adults. Serum angiotensin converting enzyme activities in patients were higher than those of the control group (p<0.05). Angiotensin converting enzyme genotype frequencies in patients were observed as 28.2%, 18% and 53.8% for DD, II and ID polymorphism, respectively. These frequencies in controls were 42.5%, 20.5% and 37% for DD, II and ID, respectively. Serum angiotensin converting enzyme activities in both groups with II genotype were significantly lower than those with ID and DD genotype (p<0.05). Although conflicting results have been reported about this polymorphism in patients with peripheral vascular disease, we suggest that the angiotensin converting enzyme ID genotype may be a risk factor for peripheral vascular disease.
Assuntos
Peptidil Dipeptidase A/genética , Doenças Vasculares Periféricas/enzimologia , Doenças Vasculares Periféricas/genética , Polimorfismo Genético , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Homozigoto , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Matrix metalloproteinases (MMPs) are extracellular matrix-modifying enzymes that are important in many physiologic and pathologic vascular processes. Dysregulation of MMP activity has been associated with common vascular diseases such as atherosclerotic plaque formation, abdominal aortic aneurysms, and critical limb ischemia. For this reason, MMPs have become an important focus for basic science studies and clinical investigations by vascular biology researchers. This article reviews the recent literature, summarizing our current understanding of the role of MMPs in the pathogenesis of various peripheral vascular disease states. In addition, the importance of MMPs in the future diagnosis and treatment of peripheral vascular disease is discussed.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Metaloproteinases da Matriz Secretadas/metabolismo , Doenças Vasculares Periféricas/enzimologia , Animais , Aneurisma da Aorta Abdominal/tratamento farmacológico , Aneurisma da Aorta Abdominal/enzimologia , Aterosclerose/tratamento farmacológico , Aterosclerose/enzimologia , Biomarcadores/metabolismo , Constrição Patológica/tratamento farmacológico , Constrição Patológica/enzimologia , Constrição Patológica/cirurgia , Inibidores Enzimáticos/farmacologia , Extremidades/irrigação sanguínea , Humanos , Isquemia/tratamento farmacológico , Isquemia/enzimologia , Metaloproteinases da Matriz Secretadas/antagonistas & inibidores , Doenças Vasculares Periféricas/diagnóstico , Doenças Vasculares Periféricas/tratamento farmacológico , Recidiva , Inibidores Teciduais de Metaloproteinases/metabolismo , Úlcera Varicosa/tratamento farmacológico , Úlcera Varicosa/enzimologia , Varizes/tratamento farmacológico , Varizes/enzimologia , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Trombose Venosa/tratamento farmacológico , Trombose Venosa/enzimologiaRESUMO
Abnormal mitochondrial function is present in patients with peripheral arterial disease and may contribute to its clinical manifestations. However, the specific biochemical mitochondrial defects and their association with increased oxidative stress have not been fully characterized. Gastrocnemius muscle was obtained from peripheral arterial disease patients (n = 25) and age-matched controls (n = 16) and mitochondrial parameters were measured. Complexes I through IV of the electron transport chain were individually evaluated to assess for isolated defects. Muscle was also evaluated for protein and lipid oxidative changes by measuring the levels of protein carbonyls, lipid hydroperoxides, and total 4-hydroxy-2-nonenal binding and for the activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase. Mitochondrial electron transport chain complexes I, III, and IV in arterial disease patients demonstrated significant reductions in enzymatic activities and mitochondrial respiration compared to controls. Oxidative stress biomarker analysis demonstrated significantly increased levels of protein carbonyls, lipid hydroperoxides, and 4-hydroxy-2-nonenal compared to control muscle. Antioxidant enzyme activities were altered, with a significant decrease in superoxide dismutase activity and significant increases in catalase and glutathione peroxidase. Peripheral arterial disease is associated with abnormal mitochondrial function and evidence of significant oxidative stress.