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1.
J Cardiovasc Pharmacol Ther ; 21(1): 82-92, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25944844

RESUMO

The development of diabetic macrovascular complications is a multifactorial process, and melatonin may possess cardiovascular protective properties. This study was designed to evaluate whether melatonin attenuates arteriosclerosis and endothelial permeability by suppressing the myosin light-chain kinase (MLCK)/myosin light-chain phosphorylation (p-MLC) system via the mitogen-activated protein kinase (MAPK) signaling pathway or by suppressing the myosin phosphatase-targeting subunit phosphorylation (p-MYPT)/p-MLC system in diabetes mellitus (DM). Rats were randomly divided into 4 groups, including control, high-fat diet, DM, and DM + melatonin groups. Melatonin was administered (10 mg/kg/d) by gavage for 12 weeks. The DM significantly increased the serum fasting blood glucose and lipid levels, as well as insulin resistance and endothelial dysfunction, which were attenuated by melatonin therapy to various extents. Importantly, the aortic endothelial permeability was significantly increased in DM rats but was dramatically reversed following treatment with melatonin. Our findings further indicated that hyperglycemia and hyperlipidemia enhanced the expressions of MLCK, p-MYPT, and p-MLC, which were partly associated with decreased membrane type 1 expression, increased extracellular signal-regulated kinase (ERK) phosphorylation, and increased p38 expression. However, these changes in protein expression were also significantly reversed by melatonin. Thus, our results are the first to demonstrate that the endothelial hyperpermeability induced by DM is associated with increased expressions of MLCK, p-MYPT, and p-MLC, which can be attenuated by melatonin at least partly through the ERK/p38 signaling pathway.


Assuntos
Aorta Abdominal/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Arteriosclerose/prevenção & controle , Diabetes Mellitus Experimental/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Endotélio Vascular/efeitos dos fármacos , Melatonina/farmacologia , Cadeias Leves de Miosina/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Estreptozocina , Animais , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/enzimologia , Aorta Abdominal/fisiopatologia , Doenças da Aorta/sangue , Doenças da Aorta/induzido quimicamente , Doenças da Aorta/enzimologia , Doenças da Aorta/fisiopatologia , Arteriosclerose/sangue , Arteriosclerose/induzido quimicamente , Arteriosclerose/enzimologia , Arteriosclerose/fisiopatologia , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/fisiopatologia , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/induzido quimicamente , Angiopatias Diabéticas/enzimologia , Angiopatias Diabéticas/fisiopatologia , Endotélio Vascular/diagnóstico por imagem , Endotélio Vascular/enzimologia , Endotélio Vascular/fisiopatologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Lipídeos/sangue , Masculino , Permeabilidade , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Ultrassonografia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Transplant Proc ; 45(2): 639-42, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23498803

RESUMO

UNLABELLED: The aim of this study was to explore underlying mechanisms of transplant arteriosclerosis (TA) based on intimal thickening that involve activation of vascular smooth muscle cells (VSMCs) and angiogenesis. We also examined the effects of adenovirus-mediated anti-sense extracellular signal-regulated kinase 2 (ERK2) (Adanti-ERK2) gene therapy on TA. METHODS: We employed a rat aorta transplantation model (Brown-Norway → Lewis). The animals were divided into: (1) an isograft group (n = 6), (2) an empty control group (n = 6), (3) the Ad-LacZ group (n = 6), and (4) the adanti-ERK2 group (n = 6). At 60 days after transplantation, we documented the ratio of intima/(intima + media) the isografts pathologically. Staining for α-actin and platelet-derived growth factor (PDGF)-BB was performed to analyze the migration and secretion of VSMCs. We evaluated angiogenesis and COX-2 staining. RESULT: Isografts showed normal histology; allografts from the empty control group and the Ad-LacZ group displayed typical TA lesions, while the pathology was significantly improved among the adanti-ERK2 group. The ratios of intima/(intima + media) were 7.6 ± 2.1%, 81.4% ± 6.7%, 85.9% ± 9.4%, and 15.9% ± 4.1% among the isograft group, the empty control, the Ad-LacZ, and the adanti-ERK2 groups respectively. The α-actin+ cells in the intima per field (×400) were 2.1 ± 1.1, 71.3 ± 9.2, 76.4 ± 11.3, and 34.8 ± 5.3, PDGF-BB+ cells, 0.9 ± 0.5, 28.4 ± 3.4, 29.1 ± 3.2, and 8.6 ± 1.7; COX-2+ cells in new capillaries were none, 36.3 ± 8.3, 40.9 ± 9.2, and 10.4 ± 3.9 respectively (P < .05). CONCLUSION: Intimal thickening a key feature of TA, involves activation of VSMC (proliferation, migration and secretion), and the accompanying angiogenesis. Adanti-ERK2 gene therapy modulates the mechanisms, protecting allografts against TA.


Assuntos
Adenoviridae/genética , Aorta Abdominal/transplante , Arteriosclerose/prevenção & controle , DNA Antissenso/metabolismo , Terapia Genética/métodos , Vetores Genéticos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/transplante , Neovascularização Patológica , Transdução Genética , Animais , Aorta Abdominal/enzimologia , Aorta Abdominal/patologia , Arteriosclerose/enzimologia , Arteriosclerose/genética , Arteriosclerose/patologia , Becaplermina , Movimento Celular , Proliferação de Células , Ciclo-Oxigenase 2/metabolismo , DNA Antissenso/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/transplante , Neointima , Proteínas Proto-Oncogênicas c-sis/metabolismo , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Lew
4.
Clin J Am Soc Nephrol ; 6(3): 505-11, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21127137

RESUMO

BACKGROUND AND OBJECTIVES: Circulating monocytes can be divided into functionally distinct subpopulations according to their surface expression of CD14 and CD16. Monocytes with high-level expression of both antigens (CD14(++)CD16(+), Mo2 cells) are associated with cardiovascular morbidity and mortality in hemodialysis patients. These cells express angiotensin converting enzyme (ACE) on their surface. They are involved in the association of chronic inflammation and cardiovascular disease in kidney patients. Cardiovascular morbidity results from atherosclerosis (plaque-forming, vessel occluding disease) and arteriosclerosis (loss of arterial dampening function). It is unknown whether ACE-expressing proinflammatory monocytes are related to atherosclerosis, arteriosclerosis, or both. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: During baseline examination for a prospective study on monocyte ACE expression and mortality, 60 chronic hemodialysis patients of an academic outpatient center were screened for atherosclerosis by carotid artery ultrasound, for arteriosclerosis by pulse pressure measurement, and for ACE expression on Mo2 cells by flow cytometry. RESULTS: ACE expression on Mo2 monocytes was significantly higher in patients with severe compared with those with little or no carotid atherosclerosis. Mo2 ACE correlated with a score to semiquantify atherosclerosis and remained a significant predictor of carotid plaques in multivariate analysis including the other univariately associated variables of age, hemoglobin A1c, and albumin. Mo2 ACE was not related to pulse pressure. CONCLUSIONS: ACE expression on Mo2, although being a known predictor of mortality and cardiovascular disease in end-stage renal disease patients, may act via enhancement of atherosclerosis rather than arteriosclerosis.


Assuntos
Arteriosclerose/etiologia , Aterosclerose/etiologia , Doenças das Artérias Carótidas/enzimologia , Falência Renal Crônica/terapia , Monócitos/enzimologia , Peptidil Dipeptidase A/sangue , Diálise Renal , Centros Médicos Acadêmicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Arteriosclerose/diagnóstico , Arteriosclerose/enzimologia , Arteriosclerose/fisiopatologia , Aterosclerose/diagnóstico por imagem , Aterosclerose/enzimologia , Pressão Sanguínea , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/etiologia , Doenças das Artérias Carótidas/fisiopatologia , Feminino , Citometria de Fluxo , Proteínas Ligadas por GPI/sangue , Alemanha , Humanos , Falência Renal Crônica/complicações , Modelos Lineares , Receptores de Lipopolissacarídeos/sangue , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Estudos Prospectivos , Fluxo Pulsátil , Receptores de IgG/sangue , Diálise Renal/efeitos adversos , Ultrassonografia
5.
Cardiol Rev ; 18(6): 269-74, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20926935

RESUMO

Liver X receptors (LXRs) are nuclear receptors that play a major role in the expression of genes which are involved in lipid metabolism. LXRs are part of the superfamily of steroid receptors that work to deliver metabolic signals on the transcriptional level to either suppress or activate target genes. LXRs, once ligand-activated, work by forming heterodimers with the retinoid X receptor, after which they act as transcription factors by binding to the promoter region of deoxyribonucleic acid sequences, thereby affecting gene expression. Specifically, LXR has been shown to be involved with genes that help in the modulation of lipid metabolism, therein having a significant effect on the development or propagation of atherosclerosis. This review paper will discuss the overall function of LXRs and their role in lipid metabolism, and will help identify possible therapeutic modulators of LXRs that can be used for the prevention and treatment of atherosclerosis.


Assuntos
Arteriosclerose/genética , Arteriosclerose/terapia , Expressão Gênica/genética , Metabolismo dos Lipídeos/genética , Receptores Nucleares Órfãos/genética , Arteriosclerose/enzimologia , Arteriosclerose/metabolismo , Ácidos e Sais Biliares/genética , Ácidos e Sais Biliares/metabolismo , DNA/genética , Ácidos Graxos/genética , Ácidos Graxos/metabolismo , Humanos , Hipolipemiantes/uso terapêutico , Inflamação/metabolismo , Receptores X do Fígado , Receptores Nucleares Órfãos/metabolismo
6.
Trends Cardiovasc Med ; 20(6): 204-9, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22137643

RESUMO

Genome-wide association studies (GWAS) of more than 100,000 people have revealed novel loci associated with coronary artery disease and myocardial infarction that present exciting opportunities to discover novel disease pathways. One such recently identified locus is on chromosome 10q11, near the gene for the chemokine CXCL12, which has been implicated in cardiovascular disease in both mouse and human studies. These GWAS demonstrate that CXCL12 may emerge as a potential therapeutic target for atherosclerosis and thrombosis.


Assuntos
Quimiocina CXCL12/genética , Doença da Artéria Coronariana/genética , Infarto do Miocárdio/genética , Animais , Arteriosclerose/enzimologia , Arteriosclerose/genética , Arteriosclerose/patologia , Quimiocina CXCL12/metabolismo , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/patologia , Modelos Animais de Doenças , Estudo de Associação Genômica Ampla , Humanos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia
7.
Nucleus ; 1(3): 245-8, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21327070

RESUMO

The SNF2 family of ATPases acts in the context of chromatin to regulate transcription, replication, repair and recombination. Defects in SNF2 genes cause many human diseases. For example, mutations in SMARCAL1 (also named HARP) cause Schimke immuno-osseous dysplasia (SIOD); a multi-system disorder characterized by growth defects, immune deficiencies, renal failure and other complex phenotypes. Several groups including ours recently identified SMARCAL1 as a replication stress response protein. Importantly, SMARCAL1 localizes to stalled replication forks and this localization of SMARCAL1 activity prevents DNA damage accumulation during DNA replication. We determined that SIOD-related SMARCAL1 mutants could not prevent replication-associated DNA damage in cells in which endogenous SMARCAL1 was silenced, establishing the first link between SIOD and a defect in a specific biological activity. Here, we also report that cells from patients with SIOD exhibit elevated levels of DNA damage that can be rescued by re-introduction of wild-type SMARCAL1. Our data suggest that loss of SMARCAL1 function in patients may cause DNA replication-associated genome instability that contributes to the pleiotropic phenotypes of SIOD.


Assuntos
Arteriosclerose/enzimologia , Arteriosclerose/genética , Dano ao DNA , DNA Helicases/metabolismo , Replicação do DNA/genética , Síndromes de Imunodeficiência/enzimologia , Síndromes de Imunodeficiência/genética , Síndrome Nefrótica/enzimologia , Síndrome Nefrótica/genética , Osteocondrodisplasias/enzimologia , Osteocondrodisplasias/genética , Embolia Pulmonar/enzimologia , Embolia Pulmonar/genética , DNA Helicases/deficiência , DNA Helicases/genética , Inativação Gênica , Humanos , Doenças da Imunodeficiência Primária
8.
Curr Cardiol Rep ; 11(6): 445-51, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19863869

RESUMO

Secretory phospholipase A(2) (sPLA(2)) represents a class of enzymes that hydrolyze phospholipids from cellular membranes and lipoproteins, resulting in multifarious proatherogenic actions in the vessel wall. Proatherogenic actions of sPLA(2) involve lipoprotein remodeling that facilitates proteoglycan binding and formation of lipid aggregates that are rapidly internalized by tissue macrophages. The hydrolysis of phospholipids on cell membranes generates bioactive lipids and lipolipoproteins with increased oxidative susceptibility. These particles and other bioactive lipids activate inflammatory pathways in various cells of the vessel wall. Transgenic mice overexpressing groups IIA, V, and X have increased atherosclerosis formation, whereas mice deficient in these sPLA(2) isoenzymes have less atherosclerosis formation. In apolipoprotein E knockout mice fed an atherosclerotic diet, sPLA(2) inhibition with varespladib reduced atherosclerosis formation. The potential for sPLA(2) inhibitors for preventing cardiovascular events is being investigated.


Assuntos
Arteriosclerose/enzimologia , Arteriosclerose/etiologia , Fosfolipases A2 Secretórias/metabolismo , Acetatos/farmacologia , Acetatos/uso terapêutico , Animais , Arteriosclerose/tratamento farmacológico , Progressão da Doença , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Inflamação/enzimologia , Inflamação/fisiopatologia , Lipoproteínas/metabolismo , Camundongos , Estresse Oxidativo , Fosfolipases A2 Secretórias/antagonistas & inibidores , Fosfolipídeos/metabolismo
9.
Vascular ; 17 Suppl 1: S40-4, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19426608

RESUMO

Arterial calcification is now understood to be an actively regulated process with promoters and inhibitors similar to those seen remodeling bone. It occurs in two distinct forms involving either the atherosclerotic intimal or the media. The amount of calcification found in the tibial arteries of the lower extremity is a better predictor of amputation than atherosclerosis risk factors and the ankle brachial index. We and others have recently demonstrated that matrix metalloproteinases (MMPs) play a critical role in the development of experimental arterial calcification in rodent models. The mechanisms by which MMPs may regulate arterial calcification, however, are not completely understood. While MMPs have traditionally been thought to function primarily in the degradation of extracellular matrix molecules, recent data suggest that MMPs may also function as important regulators of matrix biology, inflammation, and osteogenesis. In this review, we will examine recent data on the potential mechanisms by which MMPs may function in the control of arterial calcification.


Assuntos
Artérias/enzimologia , Arteriosclerose/enzimologia , Calcinose/enzimologia , Metaloproteinases da Matriz/fisiologia , Animais , Artérias/imunologia , Artérias/patologia , Arteriosclerose/imunologia , Arteriosclerose/patologia , Calcinose/imunologia , Calcinose/patologia , Matriz Extracelular/enzimologia , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Humanos , Inflamação , Camundongos , Modelos Animais , Ratos , Túnica Íntima/enzimologia , Túnica Íntima/imunologia , Túnica Íntima/patologia
10.
J Cardiovasc Pharmacol ; 53(1): 60-5, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19129734

RESUMO

The family of secretory phospholipase A2 (sPLA2) enzymes has been associated with inflammatory diseases and tissue injury including atherosclerosis. A-001 is a novel inhibitor of sPLA2 enzymes discovered by structure-based drug design, and A-002 is the orally bioavailable prodrug currently in clinical development. A-001 inhibited human and mouse sPLA2 group IIA, V, and X enzymes with IC50 values in the low nM range. A-002 (1 mg/kg) led to high serum levels of A-001 and inhibited PLA2 activity in transgenic mice overexpressing human sPLA2 group IIA in C57BL/6J background. In addition, the effects of A-002 on atherosclerosis in 2 ApoE mouse models were evaluated using en face analysis. (1) In a high-fat diet model, A-002 (30 and 90 mg/kg twice a day for 16 weeks) reduced aortic atherosclerosis by 50% (P < 0.05). Plasma total cholesterol was decreased (P < 0.05) by 1 month and remained lowered throughout the study. (2) In an accelerated atherosclerosis model, with angiotensin II-induced aortic lesions and aneurysms, A-002 (30 mg/kg twice a day) reduced aortic atherosclerosis by approximately 40% (P < 0.05) and attenuated aneurysm formation (P = 0.0096). Thus, A-002 was effective at significantly decreasing total cholesterol, atherogenesis, and aneurysm formation in these 2 ApoE mouse models.


Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/enzimologia , Aterosclerose/patologia , Fosfolipases A2 Secretórias/antagonistas & inibidores , Acetatos , Aneurisma , Animais , Aorta/patologia , Apolipoproteínas E/genética , Arteriosclerose/enzimologia , Proteínas Sanguíneas , Colesterol , Fosfolipases A2 do Grupo II , Humanos , Indóis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
11.
Postepy Biochem ; 55(4): 373-84, 2009.
Artigo em Polonês | MEDLINE | ID: mdl-20201350

RESUMO

Aminoacyl-tRNA synthetases (aaRS) are essential proteins of all living organisms. It is known that they ensure the fidelity of transfer of genetic information from the DNA into the protein. Not far away it occurred that their role is not confined to catalyze the attachment of amino acids to transfer RNAs and thereby establish the rules of genetic code by virtue of matching the nucleotide triplet of anticodon with cognate amino acid. aaRSs are also engaged in the other crucial cellular processes. So the disturbance of function of any of them often causes serious disorders. Therefore this proteins could be an attractive target of drugs, not only against the mentioned illnesses but also against bacterial, fungal and parasitic infections. Constant progress on this field makes aaRSs still an interesting object of researches.


Assuntos
Aminoacil-tRNA Sintetases/antagonistas & inibidores , Aminoacil-tRNA Sintetases/metabolismo , Aminoacil-tRNA Sintetases/genética , Arteriosclerose/tratamento farmacológico , Arteriosclerose/enzimologia , Doenças Autoimunes/enzimologia , Humanos , Infecções/tratamento farmacológico , Infecções/enzimologia , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/enzimologia
12.
Clin Chem ; 55(2): 229-38, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19095731

RESUMO

BACKGROUND: Inflammation is pivotal in all phases of atherosclerosis. Among the numerous inflammatory biomarkers, the largest amount of published data supports a role for C-reactive protein (CRP) as a robust and independent risk marker in the prediction of primary and secondary adverse cardiovascular events. In addition to being a risk marker, there is much evidence indicating that CRP may indeed participate in atherogenesis. CONTENT: In this review, we focus on the role of CRP in promoting atherothrombosis by discussing its effects on endothelial cells, endothelial progenitor cells, monocyte-macrophages, and smooth muscle cells. CONCLUSIONS: CRP is clearly a risk marker for cardiovascular disease and is recommended for use in primary prevention. In addition, CRP appears also to contribute to atherogenesis. However, much further research is needed, especially in appropriate animal models, to confirm the possible role of CRP in promoting atherothrombosis.


Assuntos
Arteriosclerose/metabolismo , Proteína C-Reativa/metabolismo , Animais , Arteriosclerose/sangue , Arteriosclerose/enzimologia , Proteína C-Reativa/genética , Proteína C-Reativa/fisiologia , Células Endoteliais/enzimologia , Células Endoteliais/metabolismo , Endotélio Vascular/enzimologia , Endotélio Vascular/metabolismo , Humanos , Óxido Nítrico Sintase Tipo III/metabolismo
13.
J Am Coll Cardiol ; 52(10): 843-50, 2008 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-18755348

RESUMO

OBJECTIVES: The aim of this study was to determine whether oxidative stress is increased in calcified, stenotic aortic valves and to examine mechanisms that might contribute to increased oxidative stress. BACKGROUND: Oxidative stress is increased in atherosclerotic lesions and might play an important role in plaque progression and calcification. The role of oxidative stress in valve disease is not clear. METHODS: Superoxide (dihydroethidium fluorescence and lucigenin-enhanced chemiluminescence), hydrogen peroxide H2O2 (dichlorofluorescein fluorescence), and expression and activity of pro- and anti-oxidant enzymes were measured in normal valves from hearts not suitable for transplantation and stenotic aortic valves that were removed during surgical replacement of the valve. RESULTS: In normal valves, superoxide levels were relatively low and distributed homogeneously throughout the valve. In stenotic valves, superoxide levels were increased 2-fold near the calcified regions of the valve (p < 0.05); noncalcified regions did not differ significantly from normal valves. Hydrogen peroxide levels were also markedly elevated in calcified regions of stenotic valves. Nicotinamide adenine dinucleotide phosphate oxidase activity was not increased in calcified regions of stenotic valves. Superoxide levels in stenotic valves were significantly reduced by inhibition of nitric oxide synthases (NOS), which suggests uncoupling of the enzyme. Antioxidant mechanisms were reduced in calcified regions of the aortic valve, because total superoxide dismutase (SOD) activity and expression of all 3 SOD isoforms was significantly decreased. Catalase expression also was reduced in pericalcific regions. CONCLUSIONS: This study provides the first evidence that oxidative stress is increased in calcified regions of stenotic aortic valves from humans. Increased oxidative stress is due at least in part to reduction in expression and activity of antioxidant enzymes and perhaps to uncoupled NOS activity. Thus, mechanisms of oxidative stress differ greatly between stenotic aortic valves and atherosclerotic arteries.


Assuntos
Antioxidantes/metabolismo , Estenose da Valva Aórtica/fisiopatologia , Arteriosclerose/fisiopatologia , Calcinose/fisiopatologia , Diferenciação Celular , Estresse Oxidativo , Estenose da Valva Aórtica/enzimologia , Arteriosclerose/enzimologia , Calcinose/enzimologia , Progressão da Doença , Humanos , Peróxido de Hidrogênio/metabolismo , Inflamação/fisiopatologia , NADP/metabolismo , Óxido Nítrico Sintase/metabolismo , Projetos Piloto , Fatores de Risco , Superóxidos/metabolismo
15.
Arq Bras Cardiol ; 91(1): e11-9, 2008 Jul.
Artigo em Inglês, Português | MEDLINE | ID: mdl-18660935

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 , Prognóstico
16.
Arq. bras. cardiol ; 91(1): e12-e19, jul. 2008. ilus, tab
Artigo em Inglês, Português | LILACS | ID: lil-486816

RESUMO

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/deficiência
17.
An. R. Acad. Farm ; 74(2): 181-201, abr. 2008. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-66770

RESUMO

Las enfermedades cardiovasculares (ECV) suponen la primera causa de muerteen los países desarrollados y se ha estimado que en el año 2010 también lideraránlas causas de muerte en los países en vías de desarrollo. Numerosos estudiosepidemiológicos han confirmado la relación entre colesterolemia y ECV, postulándoseque el descenso de los niveles séricos de colesterol produce una disminución de la incidencia y la prevalencia de muerte por cardiopatía isquémica yECV. Además se ha demostrado que la concentración elevada de lipoproteínas debaja densidad (LDL) es un factor de riesgo, mientras que la de lipoproteínas de altadensidad (HDL) es un factor protector frente a la ECV.Muchos autores han sugerido que esta acción beneficiosa de las HDL se debea que, unida a su molécula, existe una enzima denominada paraoxonasa (PON1).La PON1 es una enzima que presenta varias actividades in vitro: paraoxonasa, arilesterasay lactonasa. Parece inhibir la oxidación tanto de las LDL como de lasHDL y facilitar el transporte reverso del colesterol, disminuyendo así el riesgo deaterosclerosis.Su mecanismo de acción, propiedades catalíticas y sustratos naturales aun sedesconocen. Se han desarrollado algunos métodos espectrofotométricos y calorimétricospara determinar su actividad arilesterasa que aunque muy utilizados noson muy sensibles y los resultados obtenidos no son muy reproducibles. En estetrabajo se revisan muchos aspectos centrales referentes a esta enzima: mecanismosde acción, regulación por diferentes sustratos y mecanismos genéticos y dieta.Además se presenta un método que, utilizando como tampón un mimético desuero, permite obtener resultados más fiables y reproducibles de actividad arilesterasaen humanos y ratones. Por otra parte, se detectan posibles efectos de lospolimorfismos sobre los valores basales de actividad arilesterasa en individuos conriesgo cardiovascular incrementado


Cardiovascular diseases (CVD) are the first cause of death in developed countriesand it is estimated that by 2010 they will also be the leading cause of death indeveloping countries. Epidemiologic studies have demonstrated that reduction oftotal serum cholesterol decreases prevalence and death rates associated withischemic cardiopathy and CVD. Furthermore, a high concentration of LDL isconsidered a risk factor, while high levels of HDL are thought to be a protectivefactor.Many authors have suggested that HDL-bound PON1 enzyme may conferthe protective effects to HDL. PON1 is an enzyme with several in vitro activities:paraoxonase, arylesterase, and lactonase. It has been reported that PON1 inhibitsLDL and HDL peroxidation, as well as it facilitates the cholesterol reverse transport,helping to inhibit the developing of atherosclerosis.Its native substrates, its in vivo mechanism of action and its moleculartargets in the human body are still unknown. Nevertheless, calorimetric andspectrophotometric methods, very often employed but reaching to low very precise and sensible results, to determine its arylesterase activity have been developed. Inthis paper several aspects of this enzyme such as the mechanism of action, theregulation by substrates, genes and diet, are reviewed. Moreover, we present amethod that uses a serum mimetic buffer that permits to obtain more precise andrepeatable results of the arylesterase activity in humans and mice. Furthermore therelationship between PON1 polymorphisms and arylesterase activity is also testedin subjects at increased CVD-risk


Assuntos
Humanos , Doenças Cardiovasculares/enzimologia , Enzimas/análise , Enzimas/fisiologia , Colesterol/análise , Colesterol/farmacologia , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/enzimologia , Arteriosclerose/tratamento farmacológico , Arteriosclerose/enzimologia , Polimorfismo Genético , Lipoproteínas LDL/química , Colesterol/farmacocinética , Fatores de Risco , Lipoproteínas LDL/síntese química , LDL-Colesterol/farmacologia
18.
An. R. Acad. Farm ; 74(1): 5-27, ene. 2008. ilus
Artigo em Espanhol | IBECS | ID: ibc-65109

RESUMO

Las enfermedades cardiovasculares (ECV) suponen la primera causa de muerteen los países desarrollados y se ha estimado que en el año 2010 también lideraránlas causas de muerte en los países en vías de desarrollo. Numerosos estudiosepidemiológicos han confirmado la relación entre colesterolemia y ECV, postulándoseque el descenso de los niveles séricos de colesterol produce una disminuciónde la incidencia y la prevalencia de muerte por cardiopatía isquémica y ECV.Además se ha demostrado que la concentración elevada de lipoproteínas de bajadensidad (LDL) es un factor de riesgo, mientras que la de lipoproteínas de alta densidad(HDL) es un factor protector frente a la ECV.Muchos autores han sugerido que esta acción beneficiosa de las HDL se debea que unida a su molécula existe una enzima denominada paraoxonasa (PON1). LaPON1 es un enzima que presenta varias actividades in vitro: paraoxonasa, arilesterasa,y lactonasa. Parece inhibir la oxidación tanto de las LDL como de las HDLy facilitar el transporte reverso del colesterol, disminuyendo así el riesgo de aterosclerosis.Su mecanismo de acción, propiedades catalíticas y sustratos naturales aún sedesconocen. Se han desarrollado algunos métodos espectrofotométricos y calorimétricospara determinar su actividad arilesterasa que aunque muy utilizados noson muy sensibles y los resultados obtenidos no son muy reproducibles. En estetrabajo se revisan muchos aspectos centrales referentes a esta enzima: mecanismosde acción, regulación por diferentes sustratos y mecanismos genéticos y dieta.Además se presenta un método que utilizando como tampón un mimético de sueropermite obtener resultados más fiables y reproducibles de actividad arilesterasa enhumanos y ratones. Por otra parte, se detectan posibles efectos de los polimorfismossobre los valores basales de actividad arilesterasa en individuos con riesgocardiovascular incrementado


Cardiovascular diseases (CVD) are the first cause of death in developed countriesand it is estimated that by 2010 they will also be the leading cause of death indeveloping countries. Epidemiologic studies have demonstrated that reduction oftotal serum cholesterol decreases prevalence and death rates associated withischemic cardiopathy and CVD. Furthermore, a high concentration of LDL isconsidered a risk factor, while high levels of HDL are thought to be a protectivefactor. Many authors have suggested that HDL-bound PON1 enzyme may confer theprotective effects to HDL. PON1 is an enzyme with several in vitro activities:paraoxonase, arylesterase, and lactonase. It has been reported that PON1 inhibitsLDL and HDL peroxidation, as well as it facilitates the cholesterol reverse transport,helping to inhibit the development of atherosclerosis.Its native substrates, its in vivo mechanism of action and its molecular targetsin the human body are still unknown. Nevertheless, calorimetric andspectrophotometric methods, very often employed but reaching to low very preciseand sensible results, to determine its arylesterase activity have been developed. Inthis paper several aspects of this enzyme such as the mechanism of action, theregulation by substrates, genes and diet, are reviewed. Moreover, we present amethod that uses a serum mimetic buffer that permits to obtain more precise andreproductible results of the arylesterase activity in humans and mice. Furthermorethe relationship between PON1 polymorphisms and arylesterase activity is alsotested in subjects at increased CVD-risk


Assuntos
Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/epidemiologia , Sistema Cardiovascular/enzimologia , Polimorfismo Genético/genética , Polimorfismo Genético/fisiologia , Lipoproteínas HDL/metabolismo , Peroxidação de Lipídeos , Peroxidação de Lipídeos/fisiologia , Macrófagos/enzimologia , Fatores de Risco , Arteriosclerose/enzimologia , Arteriosclerose/prevenção & controle , Lipoproteínas HDL , Colesterol/farmacologia , Esterol Esterase/farmacologia
19.
Clín. investig. arterioscler. (Ed. impr.) ; 19(6): 287-292, nov. 2007. tab
Artigo em Espanhol | IBECS | ID: ibc-62424

RESUMO

Introducción. La paraoxonasa 1 (PON1) es una éster hidrolasa presente en las lipoproteínas de alta densidad (HDL), relacionada con la eliminación de componentes oxidados de las lipoproteínas de baja densidad (LDL) y por ello con el riesgo cardiovascular. Nuestro estudio analiza la actividad PON1 y los polimorfismos 192 y 55 del gen PON1 en los niños de edad prepuberal integrantes del Estudio Cuatro Provincias. Métodos. La población de estudio la constituyen 1.275 niños de 6 a 8 años. La actividad PON1 en suero se determinó mediante la hidrólisis de paraoxon. Los polimorfismos genéticos PON1 192Q/R y PON1 55M/L se analizaron mediante amplificación por reacción en cadena de la polimerasa (PCR) y posterior análisis de restricción. Resultados. En nuestra población la frecuencia de los alelos PON192R y PON55M es del 30 y el 38%, respectivamente, sin diferencias significativas entre provincias. La actividad PON1 es más elevada en Orense y más baja en Murcia, tanto en la población total como para cada uno de los genotipos. En la provincia de Orense se observaron correlaciones significativas entre la actividad PON1 y los valores plasmáticos de colesterol total (CT), colesterol unido a HDL (cHDL) y apolipoproteína AI (apo AI). El análisis de regresión muestra que el polimorfismo PON1 192Q/R es el principal determinante de la actividad PON1 en nuestra población. Conclusiones. La frecuencia de los polimorfismos PON192 y PON55 no difiere significativamente entre provincias. Sin embargo, a pesar de que el polimorfismo PON192 es el principal determinante de la actividad PON1, Orense presenta la actividad PON1 más alta y Murcia la más baja, lo que sugiere que ya a esta edad existen factores que regulan esa actividad dentro de cada genotipo (AU)


Background. Paraoxonase (PON1) is an ester hydrolase related to the elimination of oxidized compounds of low-density lipoprotein (LDL) particles and therefore to cardiovascular risk. The aim of the present study was to analyze the relationship between serum PON1 activity and PON1 192 and 55 polymorphisms in the prepuberal children included in the Four Provinces Study. Methods. The study population included 1,275 children aged 6 to 8 years old. Serum PON1 activity was measured by paraoxon hydrolysis. PON1 192Q/R and PON1 55M/L polymorphisms were analyzed by polymerase chain reaction and restriction analysis. Results. In the population as a whole, the prevalence of the less common PON192R allele was 30% and that of the PON55M allele was 38%, without significant differences in the frequencies between provinces. PON1 activity was highest in Orense and lowest in Murcia, both in the group as a whole and within each genotype. In Orense, significant correlations between PON1 activity and plasma total cholesterol, high-density lipoprotein cholesterol and apolipoprotein AI levels were found. Regression analysis showed that the PON1 192Q/R polymorphism is the main determinant of PON1 activity in our population. Conclusions. No significant differences between provinces in the frequencies of the PON192 and PON55 polymorphisms were found. However, although the PON192 polymorphism is the main determinant of PON1 activity, Orense showed the highest activity and Murcia the lowest for all the genotypes, suggesting that already at this age some factors are regulating PON1 activity for each genotype (AU)


Assuntos
Humanos , Masculino , Feminino , Criança , Lipoproteínas HDL/análise , HDL-Colesterol/análise , Hidrólise , Arteriosclerose/enzimologia , Fatores de Risco , Espectrofotometria/métodos , Polimorfismo Genético , Polimorfismo Genético/fisiologia , Ativação Enzimática/fisiologia , Análise de Variância , Estudos Transversais , Análise Socioeconômica , Arteriosclerose/prevenção & controle , Doença da Artéria Coronariana/prevenção & controle , Espanha/epidemiologia , Modelos Logísticos
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