RESUMO
Myeloperoxidase (MPO) is an enzyme derived of leukocytes that catalyze formation of numerous reactive oxidant species. Besides members of the innate host defense, evidences have been proving the contribution of these oxidants to tissue injury during inflammation. MPO participates in proatherogenic biological activities related to the evolution of cardiovascular disease, including initiation, propagation and acute complications of atherosclerotic process. Thereby, MPO and its inflammatory cascade represents an attractive target for prognostical investigation and therapeutics in atherosclerotic cardiovascular disease. In this review, we present the state of the art in the understanding of biological actions to clinical evidences of the relationship between MPO and coronary arterial disease. Several studies point to the independent effect of MPO levels in the evolution of disease and incidence of events in patients with acute coronary syndrome. However, the additional predictive value of MPO levels in the cardiovascular risk assessment, to incorporate it to the clinical practice as marker of plaque vulnerability, is still not consistent. Additional studies are necessary to confirm its role in the different forms of presentation of ischemic disease, besides the standardization of the assay, fundamental point for transition of this marker from research atmosphere to use in clinical routine: : from laboratory to clinical practice.
Assuntos
Doenças Cardiovasculares , Peroxidase/fisiologia , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/enzimologia , Síndrome Coronariana Aguda/etiologia , Arteriosclerose/diagnóstico , Arteriosclerose/enzimologia , Arteriosclerose/etiologia , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/etiologia , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/enzimologia , Doença da Artéria Coronariana/etiologia , Humanos , Metabolismo dos Lipídeos , Óxido Nítrico/metabolismo , Peroxidase/sangue , Peroxidase/deficiência , PrognósticoRESUMO
A mieloperoxidase (MPO) é uma enzima derivada de leucócitos que catalisa a formação de numerosas espécies reativas oxidantes. Além de integrantes da resposta imune inata, evidências têm comprovado a contribuição desses oxidantes para o dano tecidual durante inflamação. A MPO participa de atividades biológicas pró-aterogênicas relacionadas à evolução da doença cardiovascular, incluindo iniciação, propagação e as fases de complicação aguda do processo aterosclerótico. Dessa forma, a MPO e sua cascata inflamatória representam um alvo atrativo para investigação prognóstica e terapêutica na doença aterosclerótica cardiovascular. Nesta revisão, apresentamos o estado da arte no entendimento das ações biológicas às evidências clínicas da relação entre MPO e doença arterial coronariana. Vários estudos apontam para o efeito independente dos níveis de MPO na evolução da doença e ocorrência de eventos em pacientes com síndrome coronariana aguda. Entretanto, ainda não é consistente o valor preditivo adicional dos níveis de MPO na estratificação de risco cardiovascular para incorporá-la à prática clínica como sinalizadora de vulnerabilidade de placa. Estudos adicionais são necessários para confirmar seu papel nas diferentes formas de apresentação da cardiopatia isquêmica, além da padronização do ensaio, ponto fundamental para a transição desse marcador do ambiente de pesquisa para uso na rotina clínica.
Myeloperoxidase (MPO) is an enzyme derived of leukocytes that catalyze formation of numerous reactive oxidant species. Besides members of the innate host defense, evidences have been proving the contribution of these oxidants to tissue injury during inflammation. MPO participates in proatherogenic biological activities related to the evolution of cardiovascular disease, including initiation, propagation and acute complications of atherosclerotic process. Thereby, MPO and its inflammatory cascade represents an attractive target for prognostical investigation and therapeutics in atherosclerotic cardiovascular disease. In this review, we present the state of the art in the understanding of biological actions to clinical evidences of the relationship between MPO and coronary arterial disease. Several studies point to the independent effect of MPO levels in the evolution of disease and incidence of events in patients with acute coronary syndrome. However, the additional predictive value of MPO levels in the cardiovascular risk assessment, to incorporate it to the clinical practice as marker of plaque vulnerability, is still not consistent. Additional studies are necessary to confirm its role in the different forms of presentation of ischemic disease, besides the standardization of the assay, fundamental point for transition of this marker from research atmosphere to use in clinical routine: : from laboratory to clinical practice.
Assuntos
Humanos , Doenças Cardiovasculares , Peroxidase/fisiologia , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/enzimologia , Síndrome Coronariana Aguda/etiologia , Arteriosclerose/diagnóstico , Arteriosclerose/enzimologia , Arteriosclerose/etiologia , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/etiologia , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/enzimologia , Doença da Artéria Coronariana/etiologia , Metabolismo dos Lipídeos , Óxido Nítrico/metabolismo , Prognóstico , Peroxidase/sangue , Peroxidase/deficiênciaRESUMO
In the present study we investigate the effect of homocysteine (Hcy) administration, the main metabolite accumulating in homocystinuria, on butyrylcholinesterase (BuChE) activity in serum of rats. For the acute treatment, 29-day-old Wistar rats received one subcutaneous injection of Hcy (0.6 micromol/g) or saline (control) and were killed 1 h later. For the chronic treatment, Hcy was administered subcutaneously to rats from the 6th to the 28th day of life. Control rats received saline. The rats were killed 12 h after the last injection. In another set of experiments, rats were pretreated for one week with vitamins E and C or saline and 12 h after the last injection received one single injection of Hcy or saline, being killed 1 h later. Serum was used to determine BuChE activity. Our results showed that acute and chronic administration of Hcy significantly decreased BuChE activity. Furthermore, vitamins E and C per se did not alter BuChE activity, but prevented the reduction of this enzyme activity caused by acute administration of Hcy. The data suggest that the inhibitory effect of Hcy on BuChE activity is probably mediated by free radicals, since vitamins E and C administration prevented such effect.
Assuntos
Butirilcolinesterase/sangue , Regulação para Baixo/efeitos dos fármacos , Homocistinúria/enzimologia , Hiper-Homocisteinemia/enzimologia , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Arteriosclerose/enzimologia , Arteriosclerose/fisiopatologia , Ácido Ascórbico/metabolismo , Ácido Ascórbico/farmacologia , Modelos Animais de Doenças , Regulação para Baixo/fisiologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Radicais Livres/antagonistas & inibidores , Radicais Livres/metabolismo , Homocisteína/metabolismo , Homocisteína/farmacologia , Homocistinúria/sangue , Homocistinúria/tratamento farmacológico , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/tratamento farmacológico , Metabolismo dos Lipídeos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Vitamina E/metabolismo , Vitamina E/farmacologiaRESUMO
The powerful relation between atherosclerosis and diabetes may have a common genetic basis. However, few genes predisposing to both have been identified. Calpain-10 (CAPN10) was the first gene for type 2 diabetes identified by positional cloning, wherein a combination of haplotypes conferred increased risk of diabetes. We sought to determine whether CAPN10 influences subclinical atherosclerosis. Among nondiabetic subjects from 85 Mexican-American families with a history of coronary artery disease, subclinical atherosclerosis was assessed by common carotid artery intima-media thickness (IMT), insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and insulin secretion was estimated by the oral glucose tolerance test. These phenotypes were tested for association with CAPN10 haplotypes. Haplotype 1112 (of single nucleotide polymorphisms [SNPs] 44, 43, 56, and 63) was associated with increased IMT, while haplotype 1221 was associated with decreased IMT. The 112/121 haplotype combination (of SNPs 43, 56, and 63), originally found to confer increased risk for diabetes, was associated with the largest IMT in our study population. CAPN10 was also associated with both insulin sensitivity and insulin secretion. Covariate analysis suggested that CAPN10 affects IMT independently of these diabetes-related phenotypes. The fact that the diabetes gene CAPN10 also influences the risk for atherosclerosis shows that inherited factors may underlie the frequent co-occurrence of these two conditions.
Assuntos
Arteriosclerose/genética , Calpaína/genética , Adolescente , Adulto , Idoso , Arteriosclerose/enzimologia , Arteriosclerose/etnologia , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/patologia , Doença das Coronárias , Diabetes Mellitus Tipo 2/genética , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Resistência à Insulina/genética , Masculino , Americanos Mexicanos/genética , Pessoa de Meia-Idade , Fenótipo , Túnica Íntima/patologiaRESUMO
The possible association of genetic markers at the apolipoprotein E (HhaI polymorphism), apolipoprotein B (XbaI, EcoRI and Ins/Del polymorphisms), and low-density lipoprotein receptor (LDLR) (AvaII, HincII and PvuII polymorphisms) with coronary artery disease (CAD) was evaluated in 50 Brazilian women with CAD diagnosed by angiography and in 100 healthy women (controls). The frequency of E3/E4 genotype for HhaI polymorphism at the Apo E gene was significantly higher in CAD patients than in controls (40% vs. 14%, respectively, P<0.001). Similarly, the X-X- genotype for XbaI polymorphism was more frequent in CAD individuals than controls (42% vs. 12%, P<0.0001). The A+A+ and P1P1 genotypes for AvaII and PvuII polymorphisms at the LDLR locus were also higher in CAD subjects than controls (44% vs. 16%, P<0.001 and 64% vs. 39%, P<0.05, respectively). The estimated relative risks for CAD in women carrying the E3/E4, X-X-, A+A+ and P1P1 genotypes were 4.1 [95% confidence interval (CI), 3.0-5.6], 5.3 (95% CI, 3.8-7.5), 4.1 (95% CI, 3.0-5.5), and 2.8 (95% CI, 2.2-3.6), respectively. This study demonstrates that Apo E, Apo B and LDLR gene polymorphisms are associated with CAD in Brazilian Caucasian women.
Assuntos
Arteriosclerose/genética , Doença das Coronárias/diagnóstico , DNA/genética , Polimorfismo Genético , Arteriosclerose/complicações , Arteriosclerose/enzimologia , Brasil , Angiografia Coronária , Doença das Coronárias/complicações , Feminino , Genótipo , Humanos , Pessoa de Meia-IdadeRESUMO
Metalloproteinases (MTP) are enzymes that degrade the extracellular matrix, mainly collagen tissue. Normally these enzymes are expressed in vascular walls as proenzyme together with inhibitors of the active enzymes. By effect of different cytokines, produced by an inflammatory process in the vascular wall, these proenzymes are activated to an extent that surpasses the action of the inhibitors and degrade collagen. This action may partly explain the rupture of atherosclerotic plaques ("vulnerability") and also the remodelling of the vessel wall with "compensatory enlargement" of the vessel (increase in the outer size of the vessel) that allows the plaques to develop inside the arterial wall without protruding into the vessel lumen for many years. The occlusion of saphenous vein in aortocoronary bypass grafts is due to fibromuscular proliferation and atheroma development and therefore the participation of MTP in the occlusion of these vessels is a reasonable hypothesis. However, the structural features of saphenous vein bypass grafts are different from those of atheroma in native coronary arteries. Mainly the compensatory enlargement of the vessels does not occur because of intense fibrous tissue development including the adventitia and therefore the new tissue in the wall is forced to protrude into the vessel lumen. The reason for this difference in the vessel wall remodeling is not clear and the article by Grez et al in this issue of this Journal is an starting and promising study in this regard.
Assuntos
Artérias/enzimologia , Metaloendopeptidases/metabolismo , Veias/enzimologia , Arteriosclerose/enzimologia , Colágeno/metabolismo , Matriz Extracelular/enzimologia , HumanosRESUMO
BACKGROUND: The presence of metalloproteinases in atherosclerotic plaques has been described but their role is not well understood. An increased secretion of these proteolytic enzymes could explain plaque instability and distal embolization. AIM: To measure metalloproteinase activity in atherosclerotic plaques obtained after carotid endarterectomy. MATERIAL AND METHODS: Plaques were divided in one segment with and one segment without stenosis, the latter being used as control. Both segments were incubated in culture media for 48 h or were fixed for histology. The conditioned medium was studied using gelatin zimography and digital densitometry. Metalloproteinases were identified by their molecular weight, inhibition with EDTA or Western Blot. Standard histologic study and immunohistochemistry were done. RESULTS: In stenotic areas, metalloproteinase 9 (92kD) secretion was 260% higher than in regular plaques (191 and 73 Kilopixels/microgram protein respectively p < 0.02). The histological study of stenotic areas showed macrophage infiltration and neoformation of blood vessels. CONCLUSIONS: The increased secretion of cellular matrix degrading enzyme metalloproteinase 9 in stenotic areas of atherosclerotic plaques, could explain plaque instability and subsequent embolization.