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1.
Nat Rev Cardiol ; 17(2): 96-115, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31350538

RESUMO

Lysine acetylation is a conserved, reversible, post-translational protein modification regulated by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs; also known as histone deacetylases (HDACs)) that is involved in many cellular signalling pathways and diseases. Studies in animal models have revealed a regulatory role of reversible lysine acetylation in hypertension, vascular diseases, arrhythmia, heart failure and angiogenesis. Evidence from these studies indicates a therapeutic role of KDAC inhibitors (also known as HDAC inhibitors) in cardiovascular diseases. In this Review, we describe the diverse roles of KATs and KDACs in both the normal and the diseased heart. Among KDACs, class II and class III HDACs seem to have a protective role against both cardiac damage and vessel injury, whereas class I HDACs protect against vessel injury but have deleterious effects on the heart. These observations have important implications for the clinical utility of HDAC inhibitors as therapeutic agents for cardiovascular diseases. In addition, we summarize the latest data on nonacetylation acylations in the context of cardiovascular disease.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Sistema Cardiovascular/efeitos dos fármacos , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Lisina Acetiltransferases/antagonistas & inibidores , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Acetilação , Animais , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/enzimologia , Sistema Cardiovascular/fisiopatologia , Humanos , Lisina , Lisina Acetiltransferases/metabolismo , Terapia de Alvo Molecular , Transdução de Sinais
2.
Food Funct ; 10(10): 6533-6542, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31539010

RESUMO

Cardiovascular diseases are the greatest cause of death globally and are frequently associated with type 2 diabetes mellitus and metabolic syndrome, a condition including visceral obesity, hypertension, elevated triglycerides and low HDL cholesterol and hyperglycaemia. Several medicinal plants, including spices, are used in Cameroon as herbal medicines and are traditionally employed for the treatment of several ailments such as diabetes and related diseases. In this study, we chemically characterized eleven Cameroonian spice extracts and evaluated their effects on some enzyme activities relevant to carbohydrate and lipid digestion and cardio-metabolic diseases. Hydroethanolic spice extracts were characterized by GC-MS analysis and screened for their ability to modulate the activity of α-glucosidase, α-amylase, pancreatic lipase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase and angiotensin-converting enzyme (ACE). Among the spice extracts tested, those from Xylopia parviflora showed the widest inhibitory spectrum, with a relevant effect on all enzyme activities. Dichrostachys glomerata and Aframomum citratum extracts were more selective. The selected and strong activity of some plants, such as that of Aframomum citratum on pancreatic lipase and that of Xylopia aethiopica on ACE, suggests their specific use in obesity and hypertension, respectively. Chemical analysis indicated that for some spice extracts such as Xylopia parviflora and Aframomum citratum their secondary metabolites (chlorogenic acid, pimaric acid, and catechin and its derivatives) could potentially justify the biological properties observed. Our findings clearly show significant inhibition of cardio-metabolic enzymes by hydroethanolic Cameroonian spice extracts, suggesting the potential usefulness of nutraceuticals derived from these plants to develop novel management strategies for obesity and diabetes complications.


Assuntos
Doenças Cardiovasculares/enzimologia , Diabetes Mellitus Tipo 2/enzimologia , Inibidores Enzimáticos/química , Extratos Vegetais/química , Plantas Medicinais/química , Camarões , Inibidores Enzimáticos/isolamento & purificação , Humanos , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Extratos Vegetais/isolamento & purificação , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , alfa-Amilases/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
3.
Int J Clin Pract ; 73(11): e13400, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31390128

RESUMO

AIMS: Carotid femoral pulse wave velocity (CF-PWV) is associated with vascular-related diseases. However, this association has rarely been compared in the same study population, which would improve our understanding of the role of these diseases in developing arteriosclerosis. This study was designed to assess arterial function in different vascular-related diseases and the potential interrelationships between these diseases and arteriosclerosis. METHODS: There were 13 798 participants with or without established vascular-related diseases, including hypertension, diabetes, coronary artery disease (CAD), stroke and peripheral artery disease (PAD), enrolled into the study from 2010 to 2016, comprising 6648 males and 7150 females. The odds ratio (OR) of arteriosclerosis (defined as CF-PWV >12 m/s) in associations with the vascular-related diseases was modelled using multivariable logistic regression analyses to adjust for possible confounders. RESULTS: Compared with participants without vascular-related diseases, those presenting the diseases showed a significantly higher prevalence and age- and sex-adjusted OR of arteriosclerosis (all P < .001). After further adjustment for hypertension, the ORs became much smaller and not significant for CAD or stroke. Compared with apparently healthy participants, participants with each of the diseases showed a significantly higher adjusted OR (range: 2.46-3.30, all P < .001); participants with each vascular-related disease only showed much smaller and non-significant ORs, except for hypertension (OR = 2.73, 95% CI: 2.46, 3.04). After further adjustment for hypertension, these ORs became non-significant (range: 0.81-1.36, all P > .05). CONCLUSIONS AND CLINICAL IMPLICATIONS: The associations between arteriosclerosis and diseases other than hypertension were largely explained by the association with hypertension, indicating that hypertension could be the single most important factor that leads to arteriosclerosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT02569268.


Assuntos
Doenças Cardiovasculares/embriologia , Fluxo Pulsátil/fisiologia , Análise de Onda de Pulso/estatística & dados numéricos , Adulto , Idoso , Pequim , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/fisiopatologia , Doença das Coronárias , Feminino , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade
4.
Expert Opin Ther Pat ; 29(7): 555-578, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31204543

RESUMO

INTRODUCTION: Human neutrophil elastase (HNE) is involved in a variety of serious chronic diseases, especially cardiopulmonary pathologies. For this reason, the regulation of HNE activity represents a promising therapeutic approach, which is evident by the development of a number of new and selective HNE inhibitors, both in the academic and pharmaceutical environments. AREAS COVERED: The present review analyzes and summarizes the patent literature regarding human neutrophil elastase inhibitors for the treatment of cardiopulmonary diseases over 2014-2018. EXPERT OPINION: HNE is an interesting and defined target to treat various inflammatory diseases, including a number of cardiopulmonary pathologies. The research in this field is quite active, and a number of HNE inhibitors are currently in various stages of clinical development. In addition, new opportunities for HNE inhibitor development stem from recent studies demonstrating the involvement of HNE in many other inflammatory pathologies, including rheumatoid arthritis, inflammatory bowel disease, skin diseases, and cancer. Furthermore, the development of dual HNE/proteinase 3 inhibitors is being pursued as an innovative approach for the treatment of neutrophilic inflammatory diseases. Thus, these new developments will likely stimulate new and increased interest in this important therapeutic target and for the development of novel and selective HNE inhibitors.


Assuntos
Desenvolvimento de Medicamentos/métodos , Elastase de Leucócito/efeitos dos fármacos , Proteínas Secretadas Inibidoras de Proteinases/farmacologia , Animais , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/fisiopatologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Elastase de Leucócito/metabolismo , Pneumopatias/tratamento farmacológico , Pneumopatias/enzimologia , Pneumopatias/fisiopatologia , Patentes como Assunto
5.
Mol Med Rep ; 20(2): 863-870, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173191

RESUMO

CaMKII is a calcium­activated kinase, proved to be modulated by oxidation. Currently, the oxidative activation of CaMKII exists in several models of asthma, chronic rhinosinusitis with nasal polyps, cardiovascular disease, diabetes mellitus, acute ischemic stroke and cancer. Oxidized CaMKII (ox­CaMKII) may be important in several of these diseases. The present review examines the mechanism underlying the oxidative activation of CaMKII and summarizes the current findings associated with the function of ox­CaMKII in inflammatory diseases. Taken together, the findings of this review aim to improve current understanding of the function of ox­CaMKII and provide novel insights for future research.


Assuntos
Asma/enzimologia , Isquemia Encefálica/enzimologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Doenças Cardiovasculares/enzimologia , Diabetes Mellitus/enzimologia , Pólipos Nasais/enzimologia , Neoplasias/enzimologia , Sinusite/enzimologia , Animais , Asma/tratamento farmacológico , Asma/genética , Asma/patologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genética , Diabetes Mellitus/patologia , Ativação Enzimática , Expressão Gênica , Humanos , Pólipos Nasais/tratamento farmacológico , Pólipos Nasais/genética , Pólipos Nasais/patologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Oxirredução , Estresse Oxidativo , Inibidores de Proteínas Quinases/uso terapêutico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Sinusite/tratamento farmacológico , Sinusite/genética , Sinusite/patologia
6.
Arterioscler Thromb Vasc Biol ; 39(6): 1182-1190, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31070471

RESUMO

Objective- Inflammation is a causal risk factor for cardiovascular disease (CVD). sPLA2-IIA (group IIA secretory phospholipase A2) plays an integral role in regulating vascular inflammation. Although studies investigated sPLA2-IIA in secondary prevention, we prospectively evaluated sPLA2-IIA mass and genetic variants with CVD events in a primary prevention population with chronic inflammation. Approach and Results- The JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) randomized participants with LDL (low-density lipoprotein) <130 mg/dL and hsCRP (high-sensitivity C-reactive protein) ≥2 mg/L to high-intensity rosuvastatin versus placebo. Baseline and 1-year plasma sPLA2-IIA mass was measured (N=11 269 baseline; N=9620 1 year). We also identified genetic variants influencing sPLA2-IIA using genome-wide association and examined them with CVD. Three hundred thirteen incident CVD events occurred during follow-up. Baseline sPLA2-IIA mass (median, 25th-75th percentile: 3.81, 2.49-6.03 ng/mL) was associated with increased risk of CVD: risk factor-adjusted hazard ratio (95% CI; P) per SD increment: 1.22 (1.08-1.38; P=0.002). This remained significant (1.18; 1.04-1.35; P=0.01) after incrementally adjusting for hsCRP. Similar estimates were observed in rosuvastatin and placebo groups ( P treatment interaction>0.05). The rs11573156C variant in PLA2G2A (encoding sPLA2-IIA) had the strongest effect on sPLA2-II: median (25th-75th percentile, ng/mL) for CC and GG genotypes: 2.79 (1.97-4.01) and 7.38 (5.38-10.19), respectively; and had nonsignificant trend for higher CVD risk (hazard ratio, 1.11; 95% CI, 0.89-1.38; P=0.34). Conclusions- In the JUPITER population recruited on chronic inflammation, sPLA2-IIA mass was associated with CVD risk relating to vascular inflammation not fully reflected by hsCRP. Additional studies, including larger functional genetic and clinical studies, are needed to determine whether sPLA2-IIA may be a potential pharmacological target for primary prevention of CVD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00239681.


Assuntos
Doenças Cardiovasculares/enzimologia , Dislipidemias/enzimologia , Fosfolipases A2 do Grupo II/sangue , Inflamação/enzimologia , Idoso , Anti-Inflamatórios/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/prevenção & controle , Método Duplo-Cego , Dislipidemias/tratamento farmacológico , Dislipidemias/epidemiologia , Dislipidemias/genética , Feminino , Predisposição Genética para Doença , Fosfolipases A2 do Grupo II/genética , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Incidência , Inflamação/tratamento farmacológico , Inflamação/epidemiologia , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prevenção Primária , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Rosuvastatina Cálcica/uso terapêutico , Fatores de Tempo , Resultado do Tratamento
7.
Curr Pharm Des ; 25(2): 174-183, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30864507

RESUMO

BACKGROUND: Protein kinases are the enzymes involved in phosphorylation of different proteins which leads to functional changes in those proteins. They belong to serine-threonine kinases family and are classified into the AGC (Protein kinase A/ Protein kinase G/ Protein kinase C) families of protein and Rho-associated kinase protein (ROCK). The AGC family of kinases are involved in G-protein stimuli, muscle contraction, platelet biology and lipid signaling. On the other hand, ROCK regulates actin cytoskeleton which is involved in the development of stress fibres. Inflammation is the main signal in all ROCK-mediated disease. It triggers the cascade of a reaction involving various proinflammatory cytokine molecules. METHODS: Two ROCK isoforms are found in mammals and invertebrates. The first isoforms are present mainly in the kidney, lung, spleen, liver, and testis. The second one is mainly distributed in the brain and heart. RESULTS: ROCK proteins are ubiquitously present in all tissues and are involved in many ailments that include hypertension, stroke, atherosclerosis, pulmonary hypertension, vasospasm, ischemia-reperfusion injury and heart failure. Several ROCK inhibitors have shown positive results in the treatment of various disease including cardiovascular diseases. CONCLUSION: ROCK inhibitors, fasudil and Y27632, have been reported for significant efficiency in dropping vascular smooth muscle cell hyper-contraction, vascular inflammatory cell recruitment, cardiac remodelling and endothelial dysfunction which highlight ROCK role in cardiovascular diseases.


Assuntos
Doenças Cardiovasculares/enzimologia , Quinases Associadas a rho/fisiologia , Animais , Doenças Cardiovasculares/tratamento farmacológico , Humanos , Transdução de Sinais , Quinases Associadas a rho/antagonistas & inibidores
8.
Eur J Clin Invest ; 49(7): e13113, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30921469

RESUMO

BACKGROUND: Cardiovascular events are the leading cause of death in end stage renal disease (ESRD), but traditional markers of dyslipidemia are not clearly associated with cardiovascular risk in this population. Proprotein Convertase Subtilsin/Kexin type 9 (PCSK-9) could be of interest as a novel cardiovascular risk marker in ESRD due to the emergence of lipid lowering therapy based on PCSK-9 inhibition. The aim of the present study was to investigate if the convertase PCSK-9 is a potential risk marker for mortality among patients starting haemodialysis treatment. MATERIALS AND METHODS: This is a cohort study of 265 patients starting haemodialysis between 1991-2009, with 3 years follow-up. The association between baseline PCSK-9 levels and mortality was assessed using Cox proportional hazards- and quantile regression models, with adjustment for potential confounders. RESULTS: PCSK-9 levels at initiation of haemodialysis were associated to mortality in multivariable adjusted analysis. PCSK-9 levels exhibited an U-shaped association to mortality. Inclusion of the quadratic term of PCSK-9 in regression modelling optimized model performance. At baseline, PCSK-9 levels had positive correlations to Davies comorbidity score, haemoglobin and C-reactive protein while negative correlations were found for high-density lipoprotein and total cholesterol. PCSK-9 levels were higher in statin users and patients with a history of cardiovascular disease. CONCLUSIONS: This study shows, for the first time, that the level of PCSK-9 is associated with all-cause mortality in haemodialysis patients, independently of a number of potential confounders.


Assuntos
Pró-Proteína Convertase 9/metabolismo , Diálise Renal/mortalidade , Idoso , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/mortalidade , Causas de Morte , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Estudos de Coortes , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Estimativa de Kaplan-Meier , Falência Renal Crônica/enzimologia , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Transplante de Rim/mortalidade , Metabolismo dos Lipídeos/fisiologia , Masculino , Recuperação de Função Fisiológica/fisiologia , Fumar/mortalidade
10.
Int J Mol Sci ; 20(4)2019 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-30813401

RESUMO

The 90 kDa ribosomal s6 kinases (RSKs) are a group of serine/threonine kinases consisting of 4 RSK isoforms (RSK1-4), of which RSK1 is also designated as p90RSK. p90RSK plays an important role in the Ras-mitogen-activated protein kinase (MAPK) signalling cascade and is the direct downstream effector of Ras-extracellular signal-regulated kinase (ERK1/2) signalling. ERK1/2 activation directly phosphorylates and activates p90RSK, which, in turn, activates various signalling events through selection of different phosphorylation substrates. Upregulation of p90RSK has been reported in numerous human diseases. p90RSK plays an important role in the regulation of diverse cellular processes. Thus, aberrant activation of p90RSK plays a critical role in the pathogenesis of organ dysfunction and damage. In this review, we focus on the current understanding of p90RSK functions and roles in the development and progression of kidney diseases. Roles of p90RSK, as well as other RSKs, in cardiovascular disorders and cancers are also discussed.


Assuntos
Nefropatias/enzimologia , Nefropatias/patologia , Rim/enzimologia , Rim/patologia , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Animais , Doenças Cardiovasculares/enzimologia , Humanos , Neoplasias/enzimologia , Transdução de Sinais
11.
High Blood Press Cardiovasc Prev ; 26(1): 55-60, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30659516

RESUMO

INTRODUCTION: Cardiovascular diseases constitute one of the main causes of disability and premature death. The basic pathology consists of atherosclerosis. Therefore, influencing risk factors, including nutrition, is essential for prevention. AIM: To assess the opinion of Czech citizens, over 40 years old, on the role of nutrition as it relates to risk factors for cardiovascular diseases. METHODS: Data from 1992 participants were acquired using a research questionnaire administered throughout the Czech Republic from 1.4.2016-20.4.2016. The data was analyzed using the SASD program, version 1.4.12. RESULTS: Data analyses revealed that the age group in question still includes a great number of people who are unaware of the relationship between nutrition and development (31.8%) or progression (18.0%) of heart diseases. Rejection of the relationship was most frequently expressed by those 40-49 years of age and those that were employed. The study also found that the role of nutrition modification was more frequently discussed between patients and physicians (54.7%) than patients and nurses (38.0%). An overwhelming majority of respondents considered information related to nutrition modification useful (93.0%). CONCLUSION: In order to increase the efficiency of preventive measures, the transfer of theoretical knowledge to the lay public must be accompanied by interventions aimed at information repetition, motivation, and establishment of partnerships with health care providers.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Comportamento de Redução do Risco , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/fisiopatologia , República Tcheca/epidemiologia , Comportamento Alimentar , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Promoção da Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Valor Nutritivo , Prognóstico , Fatores de Proteção , Fatores de Risco , Inquéritos e Questionários
12.
Int J Mol Sci ; 20(1)2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30621010

RESUMO

The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most of these risk factors and stressors, and represents an early (subclinical) marker/predictor of atherosclerosis. Oxidative stress is a trigger of endothelial dysfunction and it is a hall-mark of cardiovascular diseases and of the risk factors/stressors that are responsible for their initiation. Endothelial function is largely based on endothelial nitric oxide synthase (eNOS) function and activity. Likewise, oxidative stress can lead to the loss of eNOS activity or even "uncoupling" of the enzyme by adverse regulation of well-defined "redox switches" in eNOS itself or up-/down-stream signaling molecules. Of note, not only eNOS function and activity in the endothelium are essential for vascular integrity and homeostasis, but also eNOS in perivascular adipose tissue plays an important role for these processes. Accordingly, eNOS protein represents an attractive therapeutic target that, so far, was not pharmacologically exploited. With our present work, we want to provide an overview on recent advances and future therapeutic strategies that could be used to target eNOS activity and function in cardiovascular (and other) diseases, including life style changes and epigenetic modulations. We highlight the redox-regulatory mechanisms in eNOS function and up- and down-stream signaling pathways (e.g., tetrahydrobiopterin metabolism and soluble guanylyl cyclase/cGMP pathway) and their potential pharmacological exploitation.


Assuntos
Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/terapia , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Epigênese Genética , Humanos , Modelos Biológicos , Oxirredução , Fatores Socioeconômicos
13.
Thromb Haemost ; 119(3): 359-367, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30605918

RESUMO

Since increased cholesterol levels are crucial in determining the development of atheroma, their reduction represents a mainstay in primary and secondary cardiovascular prevention. The most recent spectacular advancement in cholesterol-lowering therapy is represented by proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors. Although their benefit over currently available treatments has been ascribed primarily to their strong low-density lipoprotein (LDL)-cholesterol reducing action, several clues suggest that PCSK9 inhibitors may also influence platelet function and blood coagulation. PCSK9 knockout mice develop less venous and arterial thrombosis and show reduced in vivo platelet activation upon arterial injury. In patients with acute coronary syndromes (ACSs) treated with P2Y12 inhibitors, a direct association between PCSK9 serum levels and residual platelet reactivity was found. A direct correlation between urinary excretion of 11-dehydro-thromboxane-B2, a marker of in vivo platelet activation, and circulating PCSK9 levels was reported in patients with atrial fibrillation. Moreover, recombinant human PCSK9 added in vitro to human platelets potentiated activation induced by weak agonists. Finally, blood clotting factor VIII (FVIII), which is associated with stroke and ACS risk, is cleared from the circulation by members of the LDL receptor (LDLR) family. Given that PCSK9 degrades LDLR, it is conceivable that PCSK9 inhibitors by enhancing the expression of LDLR may slightly decrease circulating FVIII, in this way contributing to the prevention of cardiovascular events. This review aims to discuss the possible and hypothetical interactions between PCSK9 and the haemostatic system and to examine the possible pleiotropic effects of PCSK9 inhibitors in cardiovascular prevention.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Dislipidemias/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Hemostasia/efeitos dos fármacos , Lipídeos/sangue , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico , Animais , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/epidemiologia , Dislipidemias/sangue , Dislipidemias/enzimologia , Dislipidemias/epidemiologia , Fibrinolíticos/efeitos adversos , Humanos , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/uso terapêutico , Pró-Proteína Convertase 9/metabolismo , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
14.
J Clin Lab Anal ; 33(1): e22628, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30043502

RESUMO

BACKGROUND: Lp-PLA2 is a novel inflammation marker in cardiovascular disease. While several manufactures have registered Lp-PLA2 activity reagents, few studies have investigated the consistency among these assays. In this study, we compared and recalibrated Lp-PLA2 activity assays. METHODS: Serum samples from 110 patients and 140 healthy individuals were collected for method comparison and reference interval validation, respectively. Fresh human serum pools (847 and 442 U/L) were used for recalibration. Lp-PLA2 activity was analyzed using all five assays with a Beckman AU 5800 analyzer. Passing-Bablok regression equations and Bland-Altman plots were used to estimate the relationship and bias among the results. A 2.5% confidence interval (CI) and 97.5% CI were used to establish a laboratory reference interval. RESULTS: Assay imprecision varied from 0.8%-2.9%, while the overall coincidence rates ranged from 75.5%-98.2%. Passing-Bablok regression shows excellent linear correlation between Evermed and Diasys (R2  = 0.999), while that between Diazyme and Evermed was poor (R2  = 0.846). The R2 and correlation coefficient r among assays were 0.846-0.999 and 0.8947-0.9993, respectively. The mean bias percentages ranged from -71.5%-1.6% and -2.0%-11.6% before and after recalibration. As Diazyme and Diasys were not comparable, the Diazyme assay was not recalibrated. The reference intervals determined for Diasys, Evermed, Hengxiao, and Zybio were 184-605, 208-704, 81-328, and 273-696 U/L, respectively. CONCLUSIONS: Our results indicate that recalibration increased assay agreement and also highlight the need for each laboratory to establish its own reference interval for Lp-PLA2 activity.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase , Análise Química do Sangue , Ensaios Enzimáticos , 1-Alquil-2-acetilglicerofosfocolina Esterase/sangue , 1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Adulto , Idoso , Análise Química do Sangue/métodos , Análise Química do Sangue/normas , Calibragem , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/enzimologia , Estudos de Casos e Controles , China , Ensaios Enzimáticos/métodos , Ensaios Enzimáticos/normas , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Padrões de Referência , Reprodutibilidade dos Testes
15.
Curr Drug Metab ; 20(1): 72-82, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30112987

RESUMO

BACKGROUND: Statins have been a major keystone in the management of patients with atherosclerotic cardiovascular disease. The benefits of inhibiting HMG CoA reductase, via statins, were translated into reduction in LDL-c with proportionate decrease in cardiovascular events in response to the magnitude of LDL-c reduction. Despite major advances in pharmacological treatments, including the use of high-dose statins, there are urgent need to further reduce future cardiovascular risk. This is in particularly important since 1 out of 5 high-risk atherosclerotic patients who achieve low LDL-c return with a second cardiovascular event within five years. Although this residual risk post-statin is largely heterogeneous, lowering LDL-c beyond 'normal' or guidelines-recommended level using novel therapies has resulted in further reduction in cardiovascular events. OBJECTIVE: The current review will discuss the use of PCSK9 inhibitors in patients with atherosclerotic disease. PCSK9 inhibitors are a new class of lipid-lowering drugs that are either fully human monoclonal antibodies (evolocumab and alirocumab) or humanised monoclonal antibodies (bococizumab) that effectively reduce LDL-c to unprecedented level. By blocking circulating PCSK9, these drugs would preserve LDL receptors and prevent them from cellular degradation. This process promotes recycling of LDL receptors back to hepatocytes surface, leading into further reduction of LDL-c. Combining PCSK9 inhibitors with statin have led into lower LDL-c, reduction in plaque volume and more importantly reduction in future cardiovascular events. CONCLUSION: These drugs are very promising, nonetheless, the unselective approach of applying these monoclonal antibodies may not prove to be cost-effective and potentially exposing some patients to unnecessary side effects.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico , Animais , Doenças Cardiovasculares/enzimologia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores de Serino Proteinase/farmacologia
16.
Eur J Pharmacol ; 842: 345-350, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30439363

RESUMO

Sialic acid residues are frequently located at the terminal positions of glycoconjugate chains of cellular glycocalyx. Sialidases, or neuraminidases, catalyse removal of these residues thereby modulating various normal and pathological cellular activities. Recent studies have revealed the involvement of sialidases in a wide range of human disorders, including neurodegenerative disorders, cancers, infectious diseases and cardiovascular diseases. The accumulating data make sialidases an interesting potential therapeutic target. Modulating the activity of these enzymes may have beneficial effects in several pathologies. Four types of mammalian sialidases have been described: NEU1, NEU2, NEU3 and NEU4. They are encoded by different genes and characterized by different subcellular localization. In this review, we will summarize the current knowledge on the roles of different sialidases in pathological conditions.


Assuntos
Doença , Neuraminidase/metabolismo , Animais , Doenças Cardiovasculares/enzimologia , Humanos , Neoplasias/enzimologia , Doenças do Sistema Nervoso/enzimologia
17.
Clin Chim Acta ; 488: 143-149, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30414434

RESUMO

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a novel inflammatory biomarker, which is useful as an adjunct identification tool for cardiovascular disease. However, the important limitation of the conventional enzyme-linked immunosorbent assay (PLAC ELISA) for Lp-PLA2 assay is its relatively low sensitivity and time consuming. A method to measure the Lp-PLA2 simply, rapidly and sensitively is essential for predicting cardiovascular events in clinic. METHODS: We took advantage of magnetic separation integrated with chemiluminescence to detect Lp-PLA2. The concentration of Lp-PLA2 was measured through a one-step process by mixing antibody labelled magnetic beads, antigen and antibody at one time. RESULTS: Our method realized the sample to answer within 17 min. The detection limit and measurement range were 0.18 ng/ml and 0.18-1350 ng/ml, respectively. The specificity assay showed that no appreciable interference was observed for the substances of bilirubin, triglyceride, hemoglobin, rheumatoid factor and human anti-mouse antibody up to the concentrations of 40 mg/dl, 1000 mg/dl, 2000 mg/dl, 1500 IU/ml and 30 ng/ml, separately. We also tested 122 clinical samples using our method, presenting good overall correlations (R2 = 0.979) to the PLAC ELISA. It is worth mentioning that, our method was faster, had a wider range of measurement and higher sensitivity compared with the PLAC ELISA. CONCLUSIONS: The Lp-PLA2 assay is straightforward, sensitive and precise, which is highly suitable to further explore the clinical performance of Lp-PLA2 in studies of cardiovascular risk management.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/sangue , Doenças Cardiovasculares/enzimologia , Sistema Cardiovascular/enzimologia , Imunoensaio , Luminescência , Medições Luminescentes , 1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Doenças Cardiovasculares/sangue , Ensaio de Imunoadsorção Enzimática , Humanos , Fatores de Risco
18.
Clin Rheumatol ; 38(5): 1329-1337, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30588556

RESUMO

BACKGROUND: Atherosclerosis leading to cardiovascular disease (CVD) is the main cause of mortality and morbidity in patients with rheumatoid arthritis (RA). Paraoxonase1 (PON1) is the best understood member of plasma paraoxonases with anti-atherogenic properties. PATIENTS AND METHODS: Spanish RA (n = 549) consecutively recruited from 1 single center and 477 ethnically matched healthy controls were included in a case-control study. The concentration of PON1 was evaluated by means of an enzyme-linked immunosorbent sssay (ELISA). An arylesterase/paraoxonase assay kit was used to evaluate PON1 activity. Sample genotyping was performed by using TaqMan assays-on-demand. All results were expressed as medians ± interquartile range. One-way ANOVA comparisons were done using a nonparametric Kruskall-Wallis test. P values under 0.05 were considered to be significant. RESULTS: The concentration of PON1 in the RA group was higher than in control group (p = 0.0003), although the differences were not significant when PON1 activities were compared between both groups. No significant differences were found related to distributions of rs662 genotypes in RA patients compared to healthy controls. Among rs854860 polymorphisms, overall genotype was widely distributed between RA patients and controls. Overall PON1 concentration in plasma was not significantly different between individuals carrying any of rs662 (p = 0.8501) or rs854860 (p = 0.2741) polymorphisms. Although PON1 levels were not associated with any of the SNPs in the study, differences appear when enzyme activities are compared for each SNP separately. CVD in RA patients correlate with increased PON1 levels and lower PON1 activity. CONCLUSIONS: Although protective role of PON1 against oxidative damage in vivo could be related to other activities, in our study arylesterase activity was useful to identify phenotypic differences with emphasis placed on two SNPs coding for nonconservative amino acid changes in the functional protein.


Assuntos
Artrite Reumatoide/complicações , Artrite Reumatoide/enzimologia , Arildialquilfosfatase/metabolismo , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/etiologia , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Antioxidantes/metabolismo , Artrite Reumatoide/genética , Arildialquilfosfatase/genética , Doenças Cardiovasculares/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Espanha
19.
Cell Physiol Biochem ; 51(2): 729-745, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30463058

RESUMO

G protein-coupled receptor kinase 2 (GRK2), as a vital Ser/Thr kinase, is an important regulatory protein in the inflammatory immune response (IIR) by maintaining the balance between the function of inflammatory immune cells and non-conventional inflammatory immune cells and regulating inflammatory immune cell infiltration, inflammatory cytokine secretion, and the signaling associated with endothelial function. However, the imbalance of GRK2 expression and activity plays an important role in the development of IIR-related diseases, such as hypertension, heart failure, Alzheimer's disease, type 2 diabetes mellitus, insulin resistance, rheumatoid arthritis, thyroid cancer, multiple sclerosis, and liver cancer. Small molecule GRK2 inhibitors, including balanol, Takeda inhibitors, paroxetine and derivatives, M119 and gallein, peptides, RNA aptamers, Raf kinase inhibitory protein, and microRNAs, that can directly inhibit GRK2 kinase activity have been identified by different strategies. This review discusses recent progress in one of the hallmark molecular abnormalities of GRK2 in IIR-related diseases and explores the soft regulation of IIR by innovative drugs reducing the excessive activity of GRK2 to basal levels, without damaging normal physiological function, to ameliorate inflammatory disorders.


Assuntos
Doenças Cardiovasculares/enzimologia , Desenvolvimento de Medicamentos , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/imunologia , Quinase 2 de Receptor Acoplado a Proteína G/antagonistas & inibidores , Humanos , Inflamação , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
20.
Steroids ; 140: 185-195, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30399365

RESUMO

Cholic acid is the endogenous 12α-hydroxylated bile acid, which possesses enhanced cholesterol absorption properties compared to its 12-desoxy counterpart, chenodeoxycholic acid. The oxysterol 12α-hydroxylase enzyme is cytochrome P450 8B1 (P450 8B1), which regioselectively and stereoselectively incorporates the 12α-hydroxy group in 7α-hydroxycholest-4-en-3-one, the biosynthetic precursor of cholic acid. Despite the vital role of P450 8B1 activity in cardiovascular health, research studies of other 12α-hydroxy steroid derivatives are rare. A synthetic route to incorporate a C12α-hydroxy group into the C12-methylene (-CH2-) in dehydroepiandrosterone derivatives is disclosed. The incorporation of the C12-oxygen was accomplished through a copper mediated Schönecker oxidation of an imino-pyridine intermediate, introducing the 12ß-hydroxy group. The resulting 12ß-hydroxy steroid derivative was oxidized to the C12-ketone, which was stereoselectively reduced with lithium tri-sec-butylborohydride to afford the 12α-hydroxy stereochemistry. The C7-position was oxidized to yield the various 7-keto, 7ß-hydroxy, and 7α-hydroxy derivatives. Furthermore, 7-ketodehydroepiandrosterone and 12 α-hydroxy-7-ketodehydroepiandrosterone both displayed NMDA receptor antagonistic activities at 10 µM concentrations. These C12α-hydroxy steroids will be used as tools to identify new biochemical properties of the enzymatic products of P450 8B1, the oxysterol 12α-hydroxylase.


Assuntos
Doenças Cardiovasculares/enzimologia , Obesidade/enzimologia , Oxigênio/química , Esteroide 12-alfa-Hidroxilase/metabolismo , Esteroides/síntese química , Esteroides/farmacologia , Técnicas de Química Sintética , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Esteroides/química
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