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1.
Int J Mol Sci ; 22(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34281247

RESUMO

Background: Proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) lower LDL-cholesterol and slow atherosclerosis preventing cardiovascular events. While it is known that circulating PCSK9 enhances platelet activation (PA) and that PCSK9i reduce it, the underlying mechanism is not still clarified. Methods: In a multicenter before-after study in 80 heterozygous familial hypercholesterolemia (HeFH) patients on treatment with maximum tolerated statin dose ± ezetimibe, PA, soluble-NOX2-derived peptide (sNOX2-dp), and oxidized-LDL (ox-LDL) were measured before and after six months of PCSK9i treatment. In vitro study investigates the effects of plasma from HeFH patients before and after PCK9i on PA in washed platelets (wPLTs) from healthy subjects. Results: Compared to baseline, PCSK9i reduced the serum levels of LDL-c, ox-LDL, Thromboxane (Tx) B2, sNOX2-dp, and PCSK9 (p < 0.001). The decrease of TxB2 correlates with that of ox-LDL, while ox-LDL reduction correlated with PCSK9 and sNOX2-dp delta. In vitro study demonstrated that wPLTs resuspended in plasma from HeFH after PCSK9i treatment induced lower PA and sNOX2-dp release than those obtained using plasma before PCSK9i treatment. This reduction was vanished by adding ox-LDL. ox-LDL-induced PA was blunted by CD36, LOX1, and NOX2 inhibition. Conclusions: PCSK9i treatment reduces PA modulating NOX2 activity and in turn ox-LDL formation in HeFH patients.


Assuntos
Hiperlipoproteinemia Tipo II/tratamento farmacológico , Ativação Plaquetária/efeitos dos fármacos , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/metabolismo , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol/análise , LDL-Colesterol/sangue , Ezetimiba/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/genética , Itália , Lipoproteínas LDL/análise , Lipoproteínas LDL/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Masculino , Pessoa de Meia-Idade , NADPH Oxidase 2/análise , NADPH Oxidase 2/sangue , Pró-Proteína Convertase 9/genética
2.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070931

RESUMO

It is now about 20 years since the first case of a gain-of-function mutation involving the as-yet-unknown actor in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9), was described. It was soon clear that this protein would have been of huge scientific and clinical value as a therapeutic strategy for dyslipidemia and atherosclerosis-associated cardiovascular disease (CVD) management. Indeed, PCSK9 is a serine protease belonging to the proprotein convertase family, mainly produced by the liver, and essential for metabolism of LDL particles by inhibiting LDL receptor (LDLR) recirculation to the cell surface with the consequent upregulation of LDLR-dependent LDL-C levels. Beyond its effects on LDL metabolism, several studies revealed the existence of additional roles of PCSK9 in different stages of atherosclerosis, also for its ability to target other members of the LDLR family. PCSK9 from plasma and vascular cells can contribute to the development of atherosclerotic plaque and thrombosis by promoting platelet activation, leukocyte recruitment and clot formation, also through mechanisms not related to systemic lipid changes. These results further supported the value for the potential cardiovascular benefits of therapies based on PCSK9 inhibition. Actually, the passive immunization with anti-PCSK9 antibodies, evolocumab and alirocumab, is shown to be effective in dramatically reducing the LDL-C levels and attenuating CVD. While monoclonal antibodies sequester circulating PCSK9, inclisiran, a small interfering RNA, is a new drug that inhibits PCSK9 synthesis with the important advantage, compared with PCSK9 mAbs, to preserve its pharmacodynamic effects when administrated every 6 months. Here, we will focus on the major understandings related to PCSK9, from its discovery to its role in lipoprotein metabolism, involvement in atherothrombosis and a brief excursus on approved current therapies used to inhibit its action.


Assuntos
Aterosclerose/genética , LDL-Colesterol/metabolismo , Dislipidemias/genética , Placa Aterosclerótica/genética , Pró-Proteína Convertase 9/genética , Trombose/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/enzimologia , Aterosclerose/patologia , Plaquetas/efeitos dos fármacos , Plaquetas/enzimologia , Plaquetas/patologia , LDL-Colesterol/antagonistas & inibidores , Dislipidemias/tratamento farmacológico , Dislipidemias/enzimologia , Dislipidemias/patologia , Fibrinolíticos/uso terapêutico , Regulação da Expressão Gênica , Humanos , Hipolipemiantes/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/enzimologia , Placa Aterosclerótica/patologia , Ativação Plaquetária/efeitos dos fármacos , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/biossíntese , RNA Interferente Pequeno/uso terapêutico , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transdução de Sinais , Trombose/enzimologia , Trombose/patologia , Trombose/prevenção & controle
3.
Int J Mol Sci ; 21(14)2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679712

RESUMO

Platelet hyperactivation is involved in the established prothrombotic condition of metabolic diseases such as Type 2 Diabetes Mellitus (T2DM) and familial hypercholesterolemia (HC), justifying the therapy with aspirin, a suppressor of thromboxane synthesis through the irreversible inhibition of cyclooxygenase-1 (COX-1), to prevent cardiovascular diseases. However, some patients on aspirin show a higher than expected platelet reactivity due, at least in part, to a pro-oxidant milieu. The aim of this study was to investigate platelet reactivity in T2DM (n = 103) or HC (n = 61) patients (aspirin, 100 mg/day) and its correlation with biomarkers of redox function including the superoxide anion scavenger superoxide dismutase (SOD) and the in vivo marker of oxidative stress urinary 8-iso-prostaglandin F2α. As results, in T2DM and HC subjects the prevalence of high on-aspirin platelet reactivity was comparable when both non-COX-1-dependent and COX-1-dependent assays were performed, and platelet reactivity is associated with a lower SOD activity that in a stepwise linear regression appears as the only predictor of platelet reactivity. To conclude, in T2DM and HC, similarly, the impairment of redox equilibrium associated with a decrease of SOD activity could contribute to a suboptimal response to aspirin.


Assuntos
Aspirina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Hipercolesterolemia/complicações , Inibidores da Agregação Plaquetária/uso terapêutico , Superóxido Dismutase/metabolismo , Trombose/prevenção & controle , Idoso , Aspirina/administração & dosagem , Plaquetas/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/uso terapêutico , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Hipercolesterolemia/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Inibidores da Agregação Plaquetária/administração & dosagem , Trombose/etiologia , Trombose/metabolismo , Tromboxanos/metabolismo
4.
Int J Mol Sci ; 21(2)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31963572

RESUMO

Platelets are key players in the thrombotic processes. The alterations of platelet function due to the occurrence of metabolic disorders contribute to an increased trend to thrombus formation and arterial occlusion, thus playing a major role in the increased risk of atherothrombotic events in patients with cardiometabolic risk factors. Several lines of evidence strongly correlate metabolic disorders such as obesity, a classical condition of insulin resistance, dyslipidemia, and impaired glucose homeostasis with cardiovascular diseases. The presence of these clinical features together with hypertension and disturbed microhemorrheology are responsible for the prothrombotic tendency due, at least partially, to platelet hyperaggregability and hyperactivation. A number of clinical platelet markers are elevated in obese and type 2 diabetes (T2DM) patients, including the mean platelet volume, circulating levels of platelet microparticles, oxidation products, platelet-derived soluble P-selectin and CD40L, thus contributing to an intersection between obesity, inflammation, and thrombosis. In subjects with insulin resistance and T2DM some defects depend on a reduced sensitivity to mediators-such as nitric oxide and prostacyclin-playing a physiological role in the control of platelet aggregability. Furthermore, other alterations occur only in relation to hyperglycemia. In this review, the main cardiometabolic risk factors, all components of metabolic syndrome involved in the prothrombotic tendency, will be taken into account considering some of the mechanisms involved in the alterations of platelet function resulting in platelet hyperactivation.


Assuntos
Plaquetas/fisiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/patologia , Síndrome Metabólica/complicações , Animais , Humanos , Fatores de Risco
5.
Nutr Metab Cardiovasc Dis ; 30(2): 282-291, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-31653513

RESUMO

BACKGROUND AND AIMS: In the association between hypercholesterolemia (HC) and thrombotic risk platelet hyper-reactivity plays an important role. The inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) to reduce plasma LDL-cholesterol merges as effective therapeutic strategy to prevent cardiovascular (CV) events. Aim of this study was to verify whether a treatment up to 12 months with the monoclonal antibodies (mAbs) anti-PCSK9 influences platelet function in primary HC. METHODS AND RESULTS: In patients affected by primary HC (n = 24), all on background of statin and 17 on acetyl salicylic acid (ASA), platelet function parameters were evaluated at baseline up to 12 months of treatment with the mAb anti-PCSK9 alirocumab or evolocumab. From baseline, the treatment with anti-PCSK9 mAbs: i) in ASA HC patients, significantly decreased platelet aggregation detected in platelet-rich plasma by light transmission aggregometry and in whole blood Platelet Function Analyzer-100 assay; ii) in all HC patients, significantly decreased platelet membrane expression of CD62P and plasma levels of the in vivo platelet activation markers soluble CD40 Ligand, Platelet Factor-4, and soluble P-Selectin. Furthermore, CD62P expression, and sP-Selectin, PF-4, sCD40L levels significantly correlated with serum PCSK9. CONCLUSION: Besides markedly lowering LDL-c levels, our results suggest that HC patients benefit from anti-PCSK9 mAb treatment also for reducing platelet reactivity and increasing platelet sensitivity to the inhibitory effects of aspirin. These effects on platelets could play a role in the reduction of CV event incidence in patients treated with PCSK9 inhibitors.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Plaquetas/efeitos dos fármacos , Hipercolesterolemia/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Plaquetas/metabolismo , Ligante de CD40/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/enzimologia , Itália , Masculino , Pessoa de Meia-Idade , Selectina-P/sangue , Inibidores da Agregação Plaquetária/efeitos adversos , Fator Plaquetário 4/sangue , Pró-Proteína Convertase 9/sangue , Estudos Prospectivos , Inibidores de Serino Proteinase/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
6.
Thromb Res ; 180: 74-85, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31229924

RESUMO

BACKGROUND: The incretin hormone Glucagon-like peptide 1(GLP-1) plays a pivotal role in maintaining glucose homeostasis with effects also on the cardiovascular system. GLP-1 influences platelet functions by increasing the inhibitory action of nitric oxide (NO) and reducing oxidative stress. To date, the role of hypercholesterolemia (HyC) on platelet GLP-1 effects needs to be elucidated. METHODS: Forty-five subjects with primary HyC and twenty normocholesterolemic controls (NoC) were enrolled. In platelets from all subjects, the native GLP-1 (7-36), the truncated GLP-1 (9-36) and the GLP-1 analogue Liraglutide were evaluated in their ability to interfere with the activation of NO/PKG/VASP, PI-3K/Akt e MAPK/ERK-1/2 pathways and oxidative stress. Furthermore, in HyC subjects the role of a lipid-lowering therapy with statin on GLP-1 related peptide effects on platelet function was evaluated. RESULTS: Unlike in NoC, in platelets from HyC subjects the GLP-1 related peptides GLP-1 (7-36), GLP-1 (9-36) and Liraglutide all failed to: i) increase the antiaggregating effects of NO and the NO-induced VASP-ser239 phosphorylation, ii) decrease phosphorylation levels of Akt and ERK-2 and iii) reduce reactive oxygen species (ROS) generation. The treatment with simvastatin (40 mg/die) in HyC (n = 18) significantly reduced total and LDL cholesterol levels, platelet aggregability/activation, ROS production and NO action but did not modify platelet sensitivity to the GLP-1 effects. CONCLUSION: Collectively, these results indicate that hypercholesterolemia per se is characterized by a resistance to GLP-1 effects on platelets and this impairment is not corrected by treatment with simvastatin.


Assuntos
Plaquetas/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Sinvastatina/uso terapêutico , Adulto , Plaquetas/metabolismo , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
7.
Thromb Haemost ; 119(5): 766-778, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30861546

RESUMO

BACKGROUND: The association between iron overload (IO) and risk of cardiovascular disease is controversial. Epidemiological studies have found a significant negative association of transferrin (Tf) saturation and cardiovascular events suggesting that higher body iron possibly confer a protective effect towards developing cardiovascular events. The biological mechanisms of this phenomenon are unknown. OBJECTIVE: This article investigates the role of IO on platelet reactivity. MATERIALS AND METHODS: This study was a prospective case-control study comparing 45 patients with IO, mostly characterized by the HFE gene mutations C282Y and/or H63D, with 32 healthy controls. We evaluated: (1) platelet aggregation in both platelet-rich plasma and whole blood, (2) platelet membrane expression of the activation marker CD62P, (3) activation of platelet signalling phosphoinositide 3-kinase /Akt and mitogen-activated protein kinase/extracellular signal-regulated kinases (Erk)-1/2 pathways, (4) a pattern of in vivo platelet activation markers, and (5) iron biomarker predictors of platelet reactivity. RESULTS: IO patients had significantly lower platelet aggregability, expression of CD62P and phosphorylation amounts of pAkt and pErk-2 in response to agonists. Furthermore, patients with higher Tf saturation levels were characterized by lower circulating levels of sCD40L, PDGF-BB and thromboxane B2. Platelet aggregation and activation parameters inversely correlated with Tf saturation and the stepwise multivariate regression analysis underlined the role of Tf saturation in predicting platelet reactivity. We also found that in vitro platelet exposure to diferric Tf, but not to iron-depleted TF, dose-dependently inhibited platelet function in all investigated subjects. CONCLUSION: Tf saturation is inversely associated with platelet reactivity and this could explain, at least in part, the association of high Tf and lower risk of cardiovascular diseases in IO.


Assuntos
Plaquetas/fisiologia , Doenças Cardiovasculares/epidemiologia , Hemocromatose/metabolismo , Sobrecarga de Ferro/metabolismo , Transferrina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Células Cultivadas , Feminino , Proteína da Hemocromatose/genética , Humanos , Sobrecarga de Ferro/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Ativação Plaquetária , Agregação Plaquetária , Estudos Prospectivos , Transdução de Sinais
8.
Biomed Res Int ; 2018: 6508709, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30402489

RESUMO

Background: Beside the lipid-lowering effect, statins slow the progression of atherosclerosis by exerting anti-inflammatory and platelet inhibiting effects. We investigated whether platelet inhibition by simvastatin correlates with the statin effects on lipid lowering, inflammation, oxidative stress, and endothelial and platelet activation. Methods: In hypercholesterolemic patients allocated to diet (n=20) or a 2-month treatment with diet plus 40 mg simvastatin (n=25), we evaluated platelet aggregating responses to ADP, collagen, and arachidonic acid (AA), the effect of aspirin on AA-induced aggregation, pro- and anti-inflammatory and atherogenic mediators (IL-1ß, -5, -6, -7, -8, -9, -10, -12, and -13, IFN-γ, IP-10, Eotaxin, and sRAGE), markers of endothelium (sE-selectin, VEGF, and MCP-1) and platelet activation (sP-selectin, sCD-40L, RANTES, and PDGF-bb), and oxidative stress (8-OH-2'-deoxyguanosine). Results: After treatment, beside the improvement of lipid profile, we observed the following: a reduction of platelet aggregation to ADP (p=0.0001), collagen (p=0.0001), AA (p=0.003); an increased antiaggregating effect of aspirin in the presence of AA (p=0.0001); a reduction of circulating levels of IL-6 (p=0.0034), IL-13 (p<0.0001), IFN-γ (p<0.0001), VEGF (p<0.0001), sE-selectin (p<0.0001), sCD-40L (p<0.0001), sP-selectin (p=0.003), and 8-OH-2'-deoxyguanosine (p<0.0001); an increase of IL-10 and sRAGEs (p=0.0001 for both). LDL-cholesterol levels (i) positively correlated with IL-6, IFN-γ, E-selectin, sCD-40L, 8-OH-2'-deoxyguanosine, platelet aggregation to ADP, collagen, AA, and aspirin IC-50 and (ii) negatively correlated with IL-10 and sRAGE. In multiple regression analyses, LDL-cholesterol was the strongest predictor for most parameters of platelet reactivity. Conclusion: In primary hypercholesterolemia, simvastatin treatment reduced platelet activation and subclinical inflammation and improved endothelial dysfunction. LDL-cholesterol levels were the major correlate of platelet reactivity; however, other effects of statins may contribute to reducing the progression of atherosclerosis.


Assuntos
Citocinas/sangue , Selectina E/sangue , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Selectina-P/sangue , Ativação Plaquetária/efeitos dos fármacos , Sinvastatina/administração & dosagem , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Inflamação/sangue , Inflamação/tratamento farmacológico , Masculino , Pessoa de Meia-Idade
9.
Front Physiol ; 9: 875, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30042694

RESUMO

Platelets affect myocardial damage from ischemia/reperfusion. Redox-dependent sphingosine-1-phosphate production and release are altered in diabetic platelets. Sphingosine-1-phosphate is a double-edged sword for ischemia/reperfusion injury. Therefore, we aimed to verify whether: (1) human healthy- or diabetic-platelets are cardioprotective, (2) sphingosine-1-phosphate receptors and downstream kinases play a role in platelet-induced cardioprotection, and (3) a correlation between platelet redox status and myocardial ischemia/reperfusion injury exists. Isolated rat hearts were subjected to 30-min ischemia and 1-h reperfusion. Infarct size was studied in hearts pretreated with healthy- or diabetic-platelets. Healthy-platelets were co-infused with sphingosine-1-phosphate receptor blocker, ERK-1/2 inhibitor, PI3K antagonist or PKC inhibitor to ascertain the cardioprotective mechanisms. In platelets we assessed (i) aggregation response to ADP, collagen, and arachidonic-acid, (ii) cyclooxygenase-1 levels, and (iii) AKT and ERK-phosphorylation. Platelet sphingosine-1-phosphate production and platelet levels of reactive oxygen species (ROS) were quantified and correlated to infarct size. Infarct size was reduced by about 22% in healthy-platelets pretreated hearts only. This cardioprotective effect was abrogated by either sphingosine-1-phosphate receptors or ERK/PI3K/PKC pathway blockade. Cyclooxygenase-1 levels and aggregation indices were higher in diabetic-platelets than healthy-platelets. Diabetic-platelets released less sphingosine-1-phosphate than healthy-platelets when mechanical or chemically stimulated in vitro. Yet, ROS levels were higher in diabetic-platelets and correlated with infarct size. Cardioprotective effects of healthy-platelet depend on the platelet's capacity to activate cardiac sphingosine-1-phosphate receptors and ERK/PI3K/PKC pathways. However, diabetic-platelets release less S1P and lose cardioprotective effects. Platelet ROS levels correlate with infarct size. Whether these redox alterations are responsible for sphingosine-1-phosphate dysfunction in diabetic-platelets remains to be ascertained.

10.
Thromb Haemost ; 117(6): 1115-1128, 2017 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-28405672

RESUMO

Glucagon-like peptide 1 (GLP-1) is object of intensive investigation for not only its metabolic effects but also the protective vascular actions. Since platelets exert a primary role in the pathogenesis of atherosclerosis, inflammation and vascular complications, we investigated whether GLP-1 directly influences platelet reactivity. For this purpose, in platelets from 72 healthy volunteers we evaluated GLP-1 receptor (GLP-1R) expression and the effects of a 15-minute incubation with the native form GLP-1(7-36), the N-terminally truncated form GLP-1(9-36) and the GLP-1 analogue Liraglutide (100 nmol/l) on: i) aggregation induced by collagen or arachidonic acid (AA); ii) platelet function under shear stress; iii) cGMP and cAMP synthesis and cGMP-dependent protein kinase (PKG)-induced Vasodilator-Stimulated-Phosphoprotein (VASP) phosphorylation; iv) activation of the signalling molecules Phosphatidylinositol 3-Kinase (PI3-K)/Akt and Mitogen Activated Protein Kinase (MAPK)/ERK-1/2; and v) oxidative stress. Experiments were repeated in the presence of the nitric oxide donor Na-nitroprusside. We found that platelets constitutively express GLP-1R and that, independently of GLP-1R, GLP-1(7-36), GLP-1(9-36) and Liraglutide exert platelet inhibitory effects as shown by: a) increased NO-antiaggregating effects, b) increased the activation of the cGMP/PKG/VASP pathway, c) reduced the activation of PI3-K/Akt and MAPK/ERK-2 pathways, d) reduced the AA-induced oxidative stress. When the experiments were repeated in the presence of the antagonist of GLP-1R Exendin(9-39), the platelet inhibitory effects were maintained, thus indicating a mechanism independent of GLP-1R. In conclusion, GLP-1(7-36), its degradation product GLP-1(9-36) and Liraglutide exert similar inhibitory effects on platelet activation, suggesting a potential protective effect on the cardiovascular system.


Assuntos
Plaquetas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Óxido Nítrico/metabolismo , Fragmentos de Peptídeos/metabolismo , Ativação Plaquetária , Adulto , Plaquetas/patologia , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , GMP Cíclico/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Liraglutida/farmacologia , Masculino , Proteínas dos Microfilamentos/metabolismo , Nitroprussiato/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosfoproteínas/metabolismo , Fosforilação , Transdução de Sinais
11.
Med Res Rev ; 35(5): 968-1031, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25943420

RESUMO

Postprandial dysmetabolism in type 2 diabetes (T2D) is known to impact the progression and evolution of this complex disease process. However, the underlying pathogenetic mechanisms still require full elucidation to provide guidance for disease prevention and treatment. This review focuses on the marked redox changes and inflammatory stimuli provoked by the spike in blood glucose and lipids in T2D individuals after meals. All the causes of exacerbated postprandial oxidative stress in T2D were analyzed, also considering the consequence of enhanced inflammation on vascular damage. Based on this in-depth analysis, current strategies of prevention and pharmacologic management of T2D were critically reexamined with particular emphasis on their potential redox-related rationale.


Assuntos
Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/fisiopatologia , Estresse Oxidativo , Período Pós-Prandial , Aldeídos/química , Animais , Antioxidantes/uso terapêutico , Glicemia/análise , Colesterol/química , Dieta , Dieta Mediterrânea , Carboidratos da Dieta , Gorduras na Dieta , Exercício Físico , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Hiperglicemia/patologia , Hipoglicemiantes/uso terapêutico , Inflamação , Estilo de Vida , Lipídeos/química , Oxidantes/química , Oxirredução , Oxigênio/química , Fosfolipídeos/química
12.
Biomed Res Int ; 2014: 328959, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24779009

RESUMO

A reduction of the nitric oxide (NO) action in vascular smooth muscle cells (VSMC) could play a role in the vascular damage induced by the glycaemic excursions occurring in diabetic patients; in this study, we aimed to clarify whether a short-term incubation of cultured VSMC with high glucose reduces the NO ability to increase cGMP and the cGMP ability to phosphorylate VASP at Ser-239. We observed that a 180 min incubation of rat VSMC with 25 mmol/L glucose does not impair the NO-induced cGMP increase but reduces VASP phosphorylation in response to both NO and cGMP with a mechanism blunted by antioxidants. We further demonstrated that high glucose increases radical oxygen species (ROS) production and that this phenomenon is prevented by the PKC inhibitor chelerythrine and the NADPH oxidase inhibitor apocynin. The following sequence of events is supported by these results: (i) in VSMC high glucose activates PKC; (ii) PKC activates NADPH oxidase; (iii) NADPH oxidase induces oxidative stress; (iv) ROS impair the signalling of cGMP, which is involved in the antiatherogenic actions of NO. Thus, high glucose, via oxidative stress, can reduce the cardiovascular protection conferred by the NO/cGMP pathway via phosphorylation of the cytoskeleton protein VASP in VSMC.


Assuntos
Moléculas de Adesão Celular/metabolismo , GMP Cíclico/metabolismo , Glucose/metabolismo , Proteínas dos Microfilamentos/metabolismo , Músculo Liso Vascular/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/fisiologia , Fosfoproteínas/metabolismo , Serina/metabolismo , Acetofenonas/farmacologia , Animais , Antioxidantes/metabolismo , Benzofenantridinas/farmacologia , Células Cultivadas , Masculino , Miócitos de Músculo Liso/metabolismo , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Fosforilação/fisiologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Ratos , Ratos Zucker , Espécies Reativas de Oxigênio/metabolismo
13.
Curr Pharm Des ; 20(4): 625-34, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23688016

RESUMO

This review concerns the influence of leptin on vascular smooth muscle cells (VSMC). VSMC express different isoforms of the leptin receptor (Ob-R) able to activate a wide range of intracellular signalling pathways, mediating many relevant biological actions. In particular, leptin promotes processes deeply involved in atherogenesis, such as VSMC migration, hypertrophy, proliferation, osteogenic differentiation and metalloproteinase expression. The intracellular signalling molecules involved are JAK/STAT, PI3K/Akt, ERK 1/2, p38 MAPK, mTOR, and RhoA/ROCK. Some of these leptin actions are particularly evident in stretching conditions; others are mediated by the NAD(P)H-induced increase of Reactive Oxygen Species. A leptin-induced activation of angiotensin and endothelin systems, with up-regulation of the synthesis of the two hormones and of their receptors, has also been demonstrated. Other studies, however, showed that leptin increases in VSMC the nitric oxide production by activating the inducible nitric oxide synthase, and, via nitric oxide, exerts a vasodilating effect and impairs the proliferative and vasoconstricting actions of angiotensin II. Both the potentially harmful and the potentially beneficial effects exerted by leptin in VSMC are lost in VSMC from animal models of genetically determined leptinresistance. Cultured VSMC from leptin-resistant animals are also resistant to insulin and to nitric oxide. It is not known, however, whether in human obesity, a condition characterized by hypothalamic leptin resistance and by compensatory hyperleptinemia, VSMC are sensitive or resistant to leptin: only in the first case the predictive role of circulating leptin on cardiovascular events could support a pathogenetic influence of the hormone on atherosclerosis.


Assuntos
Leptina/metabolismo , Modelos Cardiovasculares , Músculo Liso Vascular/metabolismo , Receptores para Leptina/agonistas , Transdução de Sinais , Animais , Aterosclerose/sangue , Aterosclerose/metabolismo , Aterosclerose/patologia , Movimento Celular , Proliferação de Células , Humanos , Hipertrofia , Leptina/sangue , Músculo Liso Vascular/patologia , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Receptores para Leptina/metabolismo , Regulação para Cima
14.
Int J Mol Sci ; 14(9): 18861-80, 2013 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-24065093

RESUMO

Obesity is characterized by poor collateral vessel formation, a process involving vascular endothelial growth factor (VEGF) action on vascular smooth muscle cells (VSMC). Free fatty acids are involved in the pathogenesis of obesity vascular complications, and we have aimed to clarify whether oleic acid (OA) enhances VEGF synthesis/secretion in VSMC, and whether this effect is impaired in obesity. In cultured aortic VSMC from lean and obese Zucker rats (LZR and OZR, respectively) we measured the influence of OA on VEGF-A synthesis/secretion, signaling molecules and reactive oxygen species (ROS). In VSMC from LZR we found the following: (a) OA increases VEGF-A synthesis/secretion by a mechanism blunted by inhibitors of Akt, mTOR, ERK-1/2, PKC-beta, NADPH-oxidase and mitochondrial electron transport chain complex; (b) OA activates the above mentioned signaling pathways and increases ROS; (c) OA-induced activation of PKC-beta enhances oxidative stress, which activates signaling pathways responsible for the increased VEGF synthesis/secretion. In VSMC from OZR, which present enhanced baseline oxidative stress, the above mentioned actions of OA on VEGF-A, signaling pathways and ROS are impaired: this impairment is reproduced in VSMC from LZR by incubation with hydrogen peroxide. Thus, in OZR chronically elevated oxidative stress causes a resistance to the action on VEGF that OA exerts in LZR by increasing ROS.


Assuntos
Músculo Liso Vascular/efeitos dos fármacos , Ácido Oleico/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Células Cultivadas , Peróxido de Hidrogênio/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , NADPH Oxidases/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteína Quinase C beta/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Zucker , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética
15.
Diabetes ; 61(11): 2913-21, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22837307

RESUMO

Since hyperglycemia is involved in the "aspirin resistance" occurring in diabetes, we aimed at evaluating whether high glucose interferes with the aspirin-induced inhibition of thromboxane synthesis and/or activation of the nitric oxide (NO)/cGMP/cGMP-dependent protein kinase (PKG) pathway in platelets. For this purpose, in platelets from 60 healthy volunteers incubated for 60 min with 5-25 mmol/L d-glucose or iso-osmolar mannitol, we evaluated the influence of a 30-min incubation with lysine acetylsalicylate (L-ASA; 1-300 µmol/L) on 1) platelet function under shear stress; 2) aggregation induced by sodium arachidonate or ADP; 3) agonist-induced thromboxane production; and 4) NO production, cGMP synthesis, and PKG-induced vasodilator-stimulated phosphoprotein phosphorylation. Experiments were repeated in the presence of the antioxidant agent amifostine. We observed that platelet exposure to 25 mmol/L d-glucose, but not to iso-osmolar mannitol, 1) reduced the ability of L-ASA to inhibit platelet responses to agonists; 2) did not modify the L-ASA-induced inhibition of thromboxane synthesis; and 3) prevented the L-ASA-induced activation of the NO/cGMP/PKG pathway. Preincubation with amifostine reversed the high-glucose effects. Thus, high glucose acutely reduces the antiaggregating effect of aspirin, does not modify the aspirin-induced inhibition of thromboxane synthesis, and inhibits the aspirin-induced activation of the NO/cGMP/PKG pathway. These results identify a mechanism by which high glucose interferes with the aspirin action.


Assuntos
Aspirina/farmacologia , Plaquetas/efeitos dos fármacos , GMP Cíclico/antagonistas & inibidores , Hiperglicemia/enzimologia , Óxido Nítrico/antagonistas & inibidores , Inibidores da Agregação Plaquetária/farmacologia , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Adulto , Amifostina/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/análogos & derivados , Plaquetas/enzimologia , Plaquetas/metabolismo , Moléculas de Adesão Celular/metabolismo , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Resistência a Medicamentos , Feminino , Humanos , Hiperglicemia/sangue , Hiperglicemia/metabolismo , Lisina/análogos & derivados , Lisina/farmacologia , Masculino , Proteínas dos Microfilamentos/metabolismo , Óxido Nítrico/metabolismo , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Tromboxanos/metabolismo , Vasodilatadores/farmacologia , Adulto Jovem
16.
Stem Cells Dev ; 2012 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-22272916

RESUMO

NADPH-oxidase (NOX)-dependent reactive oxygen species (ROS) production is involved in self-renewal of stem and progenitor cells. Herein, we investigated whether high glucose (25 mM/L) (HG)-dependent NOX-mediated ROS generation is involved in self-renewal of visceral adipose tissue-derived stem cells (ASCs) as well. To this end ASCs cultured in HG or normal glucose (5 mM/L) used as control, were evaluated for their stem cell identity. We demonstrated that freshly isolated ASCs are pluripotent as they differentiate into adipocytes in-vitro and form neovessels in-vivo. However, only HG-cultured ASCs expressed octamer-binding transcription factor 4 (Oct4) and Nanog and formed spheroids. The assembly of p47phox and p67phox subunits is crucial for NOX-enzymatic activity. By knock-down of p47phox the role of NOX-generated ROS in driving ASC de-differentiation has been provided. siRNA technology was also applied to demonstrate the role of Akt activity in mediating HG-induced Oct-4 and Nanog expression as well as spheroid formation. Additionally, by knock-down of Oct4 we provided further evidence that Oct4 is essential for HG-mediated stem cell identity. Soluble factors released by ASCs are key elements in their mechanism of action. We found that NOX and Akt activity are required for cytokine production by "spheroids". Finally, as HG-cultured ASCs, diabetic patient-derived ASCs expressed higher levels of Oct-4 and Nanog than ASCs derived from healthy subjects and engaged ROS and Akt activity to turn on their secretion program. Thereby, our data indicate that HG via NOX-dependent Akt activity induces ASC de-differentiation, and suggest that HG pre-conditioning might be exploited for ASC ex-vivo expansion.

17.
Neurotoxicology ; 30(3): 479-84, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19442834

RESUMO

p,p'-DDE, or ethylene, 1,1-dichloro-2,2-bis(p-chlorophenyl), is the main metabolite of the pesticide DDT, or 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane. It is an androgen receptor antagonist and testosterone hydroxylase modulator that is also more persistent than its parent compound. In a previous study we demonstrated that embryonic exposure to different doses of p,p'-DDE accelerated onset of puberty in females and reduced male reproductive behavior. In the present study we investigated the long-term effects of the exposure to p,p'-DDE on the differentiation of male Japanese quail (Coturnix japonica) limbic circuits related to male copulatory behavior: the parvocellular vasotocin (VT) system. We observed a decrease in the density of VT-immunoreactive fibers within the medial preoptic nucleus, bed nucleus of the stria terminalis, and lateral septum in p,p'-DDE-treated birds, while no differences could be detected in the magnocellular neurons of the supraoptic nucleus. In particular the lowest dose of p,p'-DDE causes the highest decrease of VT immunoreactivity. This study provides further evidence for VT system sensitivity towards endocrine disrupting chemicals and demonstrates that the VT system may be an appropriate and sensitive biomarker for early p,p'-DDE exposure in birds.


Assuntos
Antagonistas de Androgênios/toxicidade , Copulação/efeitos dos fármacos , Diclorodifenil Dicloroetileno/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Inseticidas/toxicidade , Sistema Límbico/efeitos dos fármacos , Vasotocina/metabolismo , Animais , Biomarcadores/metabolismo , Coturnix/embriologia , Feminino , Sistema Límbico/crescimento & desenvolvimento , Sistema Límbico/metabolismo , Masculino , Fatores de Tempo
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