RESUMO
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) along with their blood lipid-lowering effect exhibit anti-inflammatory and immunomodulatory activity. We studied the effects of long-term (72-h or longer) exposure of human T lymphocytes in culture to atorvastatin and rosuvastatin (5-80 nM) on their functional activity. Treatment with statins inhibited PHA/IL-2-induced proliferation of CD4+ T lymphocytes isolated from the peripheral blood of healthy donors. This was accompanied by a decrease in the relative content of cells expressing active caspase-3. Addition of mevalonate or fetal bovine serum simultaneously with statins restored proliferative activity of cells. Culturing of CD4+ T lymphocytes with statins in the presence of IL-2 did not significantly affect the expression of chemokine receptors CCR4, CCR5, CXCR3, and CXCR4. Pretreatment with statins suppressed spontaneous and SDF-1-stimulated migration of CD4+ T lymphocytes, but little changed the content of intracellular phosphorylated protein kinases Akt, p38 and p42/44 (ERK1/2). The cellular effects of "lipophilic" atorvastatin were observed at lower concentrations compared to "hydrophilic" rosuvastatin.
Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Atorvastatina/farmacologia , Linfócitos T CD4-Positivos/fisiologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Quimiotaxia de Leucócito/efeitos dos fármacos , Humanos , Receptores CCR4/metabolismo , Receptores CCR5/metabolismo , Receptores CXCR3/metabolismo , Receptores CXCR4/metabolismo , Rosuvastatina Cálcica/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
We examined the effects of 72-h exposure to atorvastatin and rosuvastatin in concentrations of 2-10 nM on the cytokine expression in LPS/IFNγ-activated monocyte/macrophages derived from peripheral blood monocytes of healthy donors by culturing in the presence of GM-CSF. Pretreatment with statins was found to inhibit cytokine production in monocytes/macrophages after activation, while the level of cytokine mRNA in cells did not decrease. The number of cells containing active caspase-3 decreased in the culture. Culturing of monocytes/macrophages with statins was accompanied by changes in cell morphology and deceleration of cell growth. Cellular effects of "lipophilic" atorvastastin were observed at lower concentration compared to "hydrophilic" rosuvastatin.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipopolissacarídeos/metabolismo , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Apoptose , Atorvastatina/farmacologia , Caspase 3/metabolismo , Proliferação de Células , Células Cultivadas , Citocinas/metabolismo , Citometria de Fluxo , Humanos , Inflamação , Interferon gama/metabolismo , Leucócitos Mononucleares/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , RNA Mensageiro/metabolismo , Rosuvastatina Cálcica/farmacologiaRESUMO
Increased concentration of lipoprotein(a) is a risk factor of coronary heart disease. lipoprotein(a) consists of LDL-like and highly polymorphic apolipoprotein(a). Here we studied the effect of lipoprotein(a)-containing sera with different apolipoprotein(a) phenotypes on lipid accumulation by THP-1 monocyte-like cells. Cholesterol concentration in lysates of THP-1 cells was significantly higher after their incubation with lipoprotein(a)-containing serum samples with low-molecular-weight phenotype of apolipoprotein(a) in comparison with samples with a high-molecular-weight apolipoprotein(a) phenotype irrespective of initial cholesterol level as well as serum concentrations of apoB-100, oxidized LDL, and circulating immune complexes. The presence of the most atherogenic small dense LDL subfractions in examined sera in addition to a low-molecular-weight apolipoprotein(a) phenotype resulted in significant elevation of cholesterol accumulation by THP-1 cells. The data obtained explain greater atherogenicity of lipoprotein(a) with low-molecular-weight apolipoprotein(a) phenotype.
Assuntos
Apolipoproteínas A/metabolismo , Colesterol/metabolismo , Apolipoproteínas/metabolismo , Meios de Cultura Livres de Soro , Humanos , Macrófagos/metabolismo , Monócitos/metabolismo , Células THP-1RESUMO
In a 2-year prospective study, prognostic significance of the blood content of IL-10-producing CD4+ T lymphocytes for progression of coronary artery atherosclerosis was assessed. Patients with verified stable angina (n=36) admitted for scheduled coronary angiography and coronary stenting were enrolled. The blood levels of CD4+FoxpP3+ Treg, CD4+IFNγ+ Th1, CD4+IL17+ Th17, CD4+IL10+ cells, sCD25, IL-10, IL-17, C-reactive protein, and lipoprotein (a) were assayed before endovascular interventions. The blood content of CD4+IL10+ T cells below 3.3% was associated with progression of coronary artery atherosclerosis (OR 12.0 (2.3, 61.0), sensitivity 77%, specificity 78%, p=0.003). No differences in other immunological parameters and common atherosclerosis risk factors in the groups were revealed. We hypothesize that the content of CD4+IL10+ T cells can be an important predictive marker for the progression of coronary atherosclerosis.
Assuntos
Angina Estável/sangue , Aterosclerose/sangue , Doença da Artéria Coronariana/sangue , Interleucina-10/sangue , Linfócitos T Reguladores/imunologia , Idoso , Angina Estável/diagnóstico por imagem , Angina Estável/imunologia , Angina Estável/patologia , Aterosclerose/diagnóstico por imagem , Aterosclerose/imunologia , Aterosclerose/patologia , Biomarcadores/sangue , Proteína C-Reativa/imunologia , Proteína C-Reativa/metabolismo , Contagem de Linfócito CD4 , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/imunologia , Doença da Artéria Coronariana/patologia , Progressão da Doença , Feminino , Humanos , Interleucina-10/imunologia , Interleucina-17/sangue , Interleucina-17/imunologia , Lipoproteína(a)/sangue , Lipoproteína(a)/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Linfócitos T Reguladores/patologia , Células Th1/imunologia , Células Th1/patologia , Células Th17/imunologia , Células Th17/patologiaRESUMO
AIM: To investigate a balance between circulating regulatory T lymphocytes (Treg) exerting antiatherogenic activity and T helper type 1 (Th1) and T helper type 17 (Th1 7) cells having proatherogenic activity in patients with stable coronary artery disease (CAD) and different degrees of coronary atherosclerosis. SUBJECTS AND METHODS: According to coronary angiography findings, 80 patients were allocated to 4 groups: 1) 18 patients with intact coronary arteries; 2) 21 with no progressive coronary atherosclerosis; 3) 16 with progressive coronary atherosclerosis (more than 50% stenosis) in the native coronary arteries; 4) 25 patients with three-vessel lesions. Groups 2 and 3 patients had undergone coronary stenting 23.8 ± 8.4 and 22.4 ± 8.7 months before their enrollment, respectively. Lymphocytes were typed by direct immunocytofluorometry: Treg was defined as CD4+CD25highCD127low and CD4+FoxP3+ lymphocytes. For CD4+IL-17a+ Th17 and CD4+INFgamma Th1 analysis, mononuclear cells were preactivated by culture. The serum levels of high-sensitivity C-reactive protein, IL-10, sCD25, and IL-17a were determined by nephelometry, chemiluminescence (Immulite) and ELISA, respectively. RESULTS: Group 4 was found to have lower Treg levels and higher Th17 levels than Group 1. The ratio of Th17/Treg proved to be higher in Groups 3 and 4 than in Group 1 and that of (Th1+Th17)/Treg was higher in Group 3 than in Group 2. The female patients had higher Tregs levels than the male ones. The Th17/Treg index turned out to be increased in patients with a history of myocardial infarction. CONCLUSION: The imbalance of pro- and anti-atherogenic lymphocyte subpopulations plays a role in the pathogenesis of CAD and is associated with progressive atherosclerosis.
Assuntos
Aterosclerose/patologia , Doença da Artéria Coronariana/patologia , Vasos Coronários/patologia , Linfócitos T Reguladores/patologia , Células Th1/patologia , Células Th17/patologia , Idoso , Angioplastia Coronária com Balão/métodos , Aterosclerose/complicações , Aterosclerose/fisiopatologia , Proteína C-Reativa/análise , Angiografia Coronária , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/terapia , Progressão da Doença , Feminino , Humanos , Interleucina-10/análise , Subpopulações de Linfócitos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Estatística como Assunto , StentsRESUMO
Leukocyte chemotaxis to the area of tissue damage is mediated by chemokines. According to the primary structure, chemokines are divided into four families, fractalkine (CX3CL1) is the only one member of CX3C family and the only membrane-bound chemokine. Fractalkine molecule includes the extracellular N-terminal chemokine domain, mucin-like rod, the transmembrane and the intracellular domains. In membrane-bound state fractalkine has the properties of an adhesion molecule. Chemokine domain of fractalkine (CDF) is released from cell membrane by proteolysis, and this soluble form acts as a chemoattractant for leukocytes expressing fractalkine receptor CX3CR1. Fractalkine is involved in development of a number of pathological processes caused by inflammation, and therefore a search for fractalkine inhibitors is very important. For this purpose we identified several antigenic determinants--the fragments of CDF, and the following peptides were synthesized--P41-52 H-Leu-Glu-Thr-Arg-Gln-His-Arg-Leu-Phe-Cys-Ala-Asp-NH2, P53-60 H-Pro-Lys-Glu-Gln-Trp-Val-Lys-Asp-NH2 and P60-71 H-Asp-Ala-Met-Gln-His-Leu-Asp-Arg-Gln-Ala-Ala-Ala-NH2. The peptide effects on adhesion and migration of human peripheral blood monocytes expressing fractalkine receptors were investigated. In the presence of CDF and P41-52 we observed the increased adhesion and migration of monocytes compared with spontaneous values. Peptides P53-60 and P60-71 significantly inhibited monocyte adhesion and migration stimulated by CDF. Since the chemotactic activity of chemokines was shown to be dependent on their binding to glycosaminoglycans of the cell surface and extracellular matrix, the effect ofpeptides on the interaction of CDF with heparin was analyzed by ELISA. Peptide P41-52 competed with CDF for heparin binding, while peptides P53-60 and P60-71 had no significant activity.
Assuntos
Adesão Celular , Movimento Celular , Quimiocina CX3CL1 , Monócitos/citologia , Fragmentos de Peptídeos , Sequência de Aminoácidos , Adesão Celular/efeitos dos fármacos , Adesão Celular/imunologia , Adesão Celular/fisiologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Movimento Celular/fisiologia , Quimiocina CX3CL1/síntese química , Quimiocina CX3CL1/química , Quimiocina CX3CL1/imunologia , Quimiotaxia de Leucócito , Humanos , Monócitos/metabolismo , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologiaRESUMO
We studied dynamics of content of subpopulation of lymphocytes including regulatory and effector T-lymphocytes as well as concentration of soluble form of interleukine-2 receptor (sCD25) in peripheral blood of patients after coronary stenting (CS) with implantation of stents with rapamycin covering (SRC). We included into the study 62 patients with stable effort II-III functional class angina. Coronary angiography (CA) was carried out in all, CS with implantation of 1 - 2 SRC - in 42 patients. Blood samples were taken before CA/CS, in 24, 48 hours, 7 days, 1 and 3 months after intervention. Content of T-, helper and cytotoxic T-cells, -, NK-, NKT-cells, activated effector T-lymphocytes (CD4+CD251owCD127high) and regulatory T-lymphocytes (CD4+CD25highCD1271ow) were measured by direct immunofluorescence and flow cytometry. CD4+ lymphocytes were isolated from mononuclear cell fraction of donor blood by magnetic separation. Content of regulatory T-lymphocytes in culture were determined by expression of a specific marker FOXP3+. Concentration of sCD25 was measured by chemiluminescent method. It was shown that content of main subpopulations of lymphocytes in blood changed after CS or CF. Blood content of regulatory T-lymphocytes and sCD25 significantly increased after 7 days and 1 month after CS but not after CA. Plasma sCD25 concentration correlated with content of regulatory T-lymphocytes in 1 month after SRC implantation. During cultivation of CD4+ lymphocytes in the presence of rapamycin we noted antiproliferative effect relative to FOXP3-cells and accumulation of regulatory +-lymphocytes. Thus implantation of SRC in coronary arteries leads to increase of number of circulating regulatory T-lymphocytes and blood concentration of sCD25. Changes of these parameters after CS can reflect peculiarities of local and systemic reaction arising in response to introduction of stent with drug covering and be significant for assessment of prognosis of the disease.
Assuntos
Angina Pectoris/terapia , Stents Farmacológicos , Receptores de Interleucina-2/sangue , Sirolimo/administração & dosagem , Linfócitos T Reguladores/metabolismo , Idoso , Angina Pectoris/diagnóstico , Angina Pectoris/metabolismo , Angina Pectoris/fisiopatologia , Angioplastia Coronária com Balão/métodos , Angiografia Coronária , Sistemas de Liberação de Medicamentos , Feminino , Citometria de Fluxo , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Prognóstico , Índice de Gravidade de Doença , Sirolimo/farmacocinéticaRESUMO
AIM: To study the effect of the anti-inflammatory peptide preparation ingramon on the peripheral blood levels of inflammatory markers in patients with exercise-induced stable angina after coronary stenting (CS). SUBJECTS AND METHODS: The investigation enrolled 64 patients with stable angina who had undergone coronary bypass surgery, of them 34 patients received ingramon in addition to standard therapy. The blood levels of high-sensitive C-reactive protein (hs-CRP), fibrinogen, the chemokines MCP-1, IL-8, IP-10, and MID were measured before and 1, 2, and 7 days and 1, 3, and 6 months after surgery. Twenty patients who had gone coronarography (CG) only were examined as a control group. RESULTS: In the post CS patients receiving only standard therapy, the levels of hs-CRP and fibrinogen were much higher on days 1, 2, and 7 after surgery than in the CG patients. On day 1 following CS, the increment in hs-CRP correlated with the length of implanted stents. During ingramon therapy, the content of hs-CRP and fibrinogen was considerably lower on days 1, 2, and 7 after CS than in the control group; this trend persisted a month after surgery; there was also a reduction in MCP-1 levels within the first 24 hours after initiation of therapy. The levels of the chemokines IP-10, MIG, and IL-8 were significantly unchanged. CONCLUSION. When added to standard therapy, ingramon exerts a positive effect against risk factors for coronary heart disease (CHD) and its events. Further investigations are required to define the impact of ingramon therapy on prognosis in patients with CHD.
Assuntos
Proteínas de Fase Aguda/análise , Angioplastia Coronária com Balão , Anti-Inflamatórios não Esteroides/uso terapêutico , Quimiocinas/sangue , Reestenose Coronária/prevenção & controle , Stents Farmacológicos , Isquemia Miocárdica/cirurgia , Fragmentos de Peptídeos/uso terapêutico , Anti-Inflamatórios não Esteroides/administração & dosagem , Reestenose Coronária/sangue , Reestenose Coronária/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/sangue , Fragmentos de Peptídeos/administração & dosagem , Resultado do TratamentoRESUMO
The effects of the synthetic monocyte chemotactic protein-1 (MCP-1) peptide fragment 65-76 (peptide X) on the development of neointima after balloon injury to the carotid artery were studied. The agent was given i.m. at a dose of 33 microg/kg once daily for 28 days after balloon injury. Animals given peptide showed significant suppression of neointima growth 4 and 7 days after lesioning, as indicated by morphometric analysis of sections of lesioned arteries. On days 14 and 28, there were no significant differences in neointima formation in rats given and not given peptide. Peptide administration was not accompanied by any changes in C-reactive peptide concentrations, leukocyte counts, or the population composition of peripheral blood lymphocytes. Use of synthetic peptide X as an inhibitor of leukocyte migration during angioplasty may, along with traditional treatments, decrease the risk of restenosis.
Assuntos
Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/tratamento farmacológico , Quimiocina CCL2/farmacologia , Peptídeos/farmacologia , Túnica Íntima/metabolismo , Animais , Proteína C-Reativa/análise , Artérias Carótidas/patologia , Lesões das Artérias Carótidas/sangue , Oclusão de Enxerto Vascular/prevenção & controle , Contagem de Leucócitos , Masculino , Ratos , Ratos WistarRESUMO
AIM: To investigate the effects of coronary stenting with rapamycin-eluting stents on parameters of cell immunity. METHODS: 26 patients (group 1) with stable coronary heart disease and angiographically proved coronary stenosis underwent stenting with rapamycin-eluting stents. The control group (group 2) consisted of 6 patients: 4 patients underwent diagnostic coronaroangiography, I patient got a bare metal stent and in 1 patient angioplasty was unsuccessful. Blood samples were obtained before and 1 month after the intervention. The quantity of activated (CD4+CD25low+) and regulatory (CD4+CD25high+) T cells was measured by direct immunofluorescence and flow cytometry. Plasma concentration of IL-10 was determined by ELISA. RESULTS: In group 1 the percentages of CD4+CD25high+ regulatory T-cells increased significantly one month after stenting, while in group 2 no difference in regulatory T-cell levels before and after the intervention was observed. No changes in total number of leukocytes, relative levels of lymphocytes, CD4+ T-cells, activated CD4+CD25+low T-cells and IL-10 plasma concentration before and after the procedure were detected in both groups. CONCLUSION: Rapamycin-eluting stent implantation is associated with a significant increase of circulating CD4+CD25high+ regulatory T-cell level.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doença das Coronárias/imunologia , Stents Farmacológicos , Sirolimo/administração & dosagem , Linfócitos T Reguladores/efeitos dos fármacos , Contagem de Células Sanguíneas , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/cirurgia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Feminino , Humanos , Interleucina-10/sangue , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/imunologiaRESUMO
AIM: To analyse contents of leukocytes and chemokines expression cytokines and transforming growth factor beta (TGFB) in atherosclerotic plaques (AP) of coronary arteries and aortic intima of patients with coronary artery disease (CAD). MATERIAL AND METHODS: The samples of aortic intima and coronary artery tissues were obtained intraoperatively (coronary artery bypass grafting, endarterectomy). Leukocytes were typed immunohistochemically and cytometry in the flow. Gene expression was analysed using reverse transcription and polymerase chain reaction. RESULTS: AP of the coronary arteries and macroscopically unaffected fragments of aortic imtima contained leukocytes. All the samples contained mRNA of chemokines SDF- 1 and MCP-3. Two groups of the plaques were identified by chemokines expression. Group I AP had marked expression of TGFB, chemokines SDF-1, MCP-3, MIG, I-309, MCP-1, MIP-1beta, I-TAC, RANTES and IL-13. Group II AP had mRNA of the proteins only in single samples. Intima samples free of morphological signs of atherosclerotic lesion contained mRNA of proinflammatory chemokines MIG, I-309, IL-13, had no expression of TGFB. CONCLUSION: In IHD patients arterial intima free of macroscopic visual affection may be a site of developing inflammation. AP differ by chemokines expression, cytokines, TGFB. The differences may indicate different stages or mechanisms of AP formation.
Assuntos
Aterosclerose/genética , Doença da Artéria Coronariana/genética , Vasos Coronários/metabolismo , Citocinas/genética , Expressão Gênica , RNA Mensageiro/genética , Aterosclerose/complicações , Aterosclerose/metabolismo , Biomarcadores/metabolismo , Quimiocinas/biossíntese , Quimiocinas/genética , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/metabolismo , Vasos Coronários/patologia , Citocinas/biossíntese , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Contagem de Leucócitos , Leucócitos/imunologia , Leucócitos/patologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
AIM: To measure and compare the level of circulating precursors of endothelial cells in patients with acute coronary non-ST-elevation syndrome (NSTES), patients with stable effort angina (SEA) before coronary stenting and after it and persons with documented absence of coronary heart disease (CHD). MATERIAL AND METHODS: The trial included 19 patients with acute coronary NSTES, 20 patients with SEA and 14 patients free of CHD. Blood samples were stained with antibodies CD45-FITC (Becton Dickinson), CD34-PerCP (Becton Dickinson), KDR-PE (R&D systems). Count of cell populations was measured with flow cytofluorimetry (FACSCalibur (Becton Dickinson). RESULTS: SEA patients had the number of circulating cells CD34+ including hematopoietic cells and endothelial precursors (EP) two times lower versus that in the controls (0.650 +/- 0.086 and 1.216 +/- 0.242%, respectively, p = 0.037). No significant differences were found by the number of CD34+KDR+ cells between the groups. A trend was found to lower number of CD34-KDR+ cells in EA patients compared to control. The differences reached significance on day 1 and 3-5 after endovascular interventions (0.067 +/- 0.022, 0.060 +/- 0.017 and 0.188 +/- 0.052%, respectively, p = 0.024 and p = 0.021). CONCLUSION: The count of blood CD34+ cells in combination with other indicators can be used as an additional factor confirming the presence of chronic myocardial ischemia.
Assuntos
Síndrome Coronariana Aguda/metabolismo , Angina Pectoris/metabolismo , Esforço Físico , Nó Sinoatrial/fisiologia , Síndrome Coronariana Aguda/sangue , Angina Pectoris/sangue , Antígenos CD34/sangue , Humanos , Antígenos Comuns de Leucócito/sangueRESUMO
The retro-enantio analogue of peptide 66-77 of the chemokine MCP-1 and two hexapeptide fragments 66-71 and 72-77 of the C-terminal sequence of this protein were synthesized using the Fmoc strategy of solid phase peptide synthesis. The effect of the synthetic peptides upon the MCP-1-stimulated migration of THP-1 mononuclear cells was studied in vitro. The activity of the retro-enantio analogue was found to be comparable with that of the initial peptide 66-77: both peptides inhibit the migration of monocytes and granulocytes into inflammation zones of experimental animals.
Assuntos
Quimiocina CCL2/química , Quimiotaxia de Leucócito/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Células Cultivadas , Quimiocina CCL2/farmacologia , Granulócitos/efeitos dos fármacos , Granulócitos/fisiologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Dados de Sequência Molecular , Monócitos/fisiologia , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/química , Peritonite/induzido quimicamente , Peritonite/imunologia , Ratos , Ratos Wistar , EstereoisomerismoRESUMO
AIM: To estimate concentrations of C-reactive protein (CRP) and MCP-1 in blood plasma of patients with unstable angina (UA) and stable effort angina (SEA). MATERIAL AND METHODS: Multiprojection coronaroangiography was performed in 12 patients with UA and 11 patients with SEA. Hemodynamically significant stenosis (50% and more) at least in one major coronary artery was confirmed in all the patients. CRP and MCP-1 were measured with latex agglutination and enzyme immunoassay (Biosource kits), respectively. RESULTS: UA patients had significantly higher plasma levels of MCP-1 and CRP than those with SEA (107.25 +/- 16.19 vs. 63.0 +/- 16.16 pg/ml and 1.99 +/- 1.64 vs 0.44 +/- 0.28 mcg/ml, respectively). CONCLUSION: Estimation of MCP-1, as a marker of vascular wall inflammation, can be used, in line with other indices, for verification of UA.
Assuntos
Angina Instável/metabolismo , Proteína C-Reativa/metabolismo , Quimiocina CCL2/metabolismo , Doença Aguda , Angina Pectoris/metabolismo , Doença das Coronárias/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
AIM: To study the condition of the sympathico-adrenal system (SAS), synthesis of cAMP dependent on beta2-adrenoreceptors and parameters of free radical oxidation in patients with primary pulmonary hypertension (PPH); to examine efficacy of non-selective beta- and alpha1-adrenoblocker carvedilol in PPH patients. MATERIAL AND METHODS: Twenty patients with PPH had 6-minute walk test, ECG monitoring with assessment of heart rhythm variability (HRV). Tests for noradrenalin and adrenalin concentration in blood plasma, cAMP synthesis by blood lymphocytes in basal conditions and under stimulation with isoproterenol and forskolin, free radical oxidation were made initially, 1 and 6 months later. Ten patients received carvedilol in addition to standard therapy, 10 patients served control. RESULTS: PPH patients had higher NA in the blood, low cAMP synthesis, high malonic aldehyde, low activity of glutathionperoxidase, increased activity of superoxidedismutase and catalase of erythrocytes. The most pronounced changes in the above parameters were observed in patients with PPH FC III-IV. HRV declined in progression of cardiac failure. 6-months of combined treatment with carvedilol increased the distance of 6-min walk. Carvedilol had no effect on HRV, it reduced NA, stimulated cAMP synthesis, demonstrated no antioxidant activity. CONCLUSION: In PPH there is activation of SAS and desensitization of beta2-AR cells, oxidative stress develops. Addition of carvedilol to standard therapy with PPH improves clinical condition due to adrenoblocking properties of the drug.
Assuntos
Adrenérgicos/farmacologia , Anti-Hipertensivos/farmacologia , Carbazóis/farmacologia , Radicais Livres/metabolismo , Hipertensão Pulmonar , Propanolaminas/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Adrenérgicos/uso terapêutico , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico , Carbazóis/uso terapêutico , Carvedilol , Catalase/sangue , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/fisiopatologia , Masculino , Malondialdeído/metabolismo , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Oxirredutases/metabolismo , Propanolaminas/uso terapêuticoRESUMO
Monocyte chemotactic protein-1 (MCP-1) is a chemokine that stimulates monocytes and macrophage migration into the sites of acute of chronic inflammation. Our study shows morphological changes in ischemic myocardium followed by the administration of two synthetic structural fragments of MCP-1 that are monocyte/macrophage migration inductor peptide IX and peptide X an inhibitor. Results show that peptides can change time points of the inflammatory response in myocardium. Peptide IX administration leads to increased and accelerated inflammatory response, i. e. attracts an additional number of monocytes and macrophages into the inflammatory focus. The introduction of the peptide X observed prolonged inflammatory process with the overall gain signs of myocardial damage.
Assuntos
Quimiocina CCL2/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Animais , Quimiocina CCL2/farmacologia , Macrófagos/efeitos dos fármacos , Masculino , Monócitos/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , RatosRESUMO
Fourteen fragments and structural analogues of chemokine MCP-1 were synthesized using the Fmoc strategy of solid phase peptide synthesis. The effect of synthesized peptides on the MCP-1-stimulated migration of mononuclear cells was examined. Both in vitro stimulants and inhibitors of the monocyte migration were found among the peptides. A possible participation of the C-terminal part of the MCP-1 molecule in the inhibition of the MCP-1-stimulated cell migration was found for the first time. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 6; see also http://www.maik.ru.
Assuntos
Quimiocina CCL2/química , Quimiocina CCL2/fisiologia , Quimiotaxia de Leucócito/fisiologia , Monócitos/fisiologia , Oligopeptídeos/síntese química , Fragmentos de Peptídeos/química , Sequência de Aminoácidos , Células Cultivadas , Quimiocina CCL2/farmacologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Humanos , Dados de Sequência Molecular , Monócitos/efeitos dos fármacos , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/farmacologia , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , EstereoisomerismoRESUMO
Monocytic cell adhesion to immobilized fibrinogen and fibrinogen degradation products, and involvement of integrins Mac-1 and immunoglobulin-like ICAM-1 adhesion molecules in these processes were investigated. Fibrinogen cleavage with plasmin down-regulated adhesion of cells with predominant Mac-1 expression; in contrast, the attachment of ICAM-1-expressing was up-regulated. By means of function-blocking anti-Mac-1 and anti-ICAM-1 antibodies, and immobilization of known fibrinogen degradation products, it was shown that Mac-1 molecules mediated cell adhesion predominantly to fibrinogen, and its early degradation products, fragments X and Y, while ICAM-1 participated in cell attachment to X- and Y-fragments, rather than to intact fibrinogen or late degradation products, fragments D and E.
Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio , Fibrinogênio , Molécula 1 de Adesão Intercelular/biossíntese , Antígeno de Macrófago 1/biossíntese , Monócitos/citologia , Adesão Celular , Linhagem Celular , Humanos , Monócitos/metabolismo , Regulação para CimaRESUMO
AIM: To examine expression of superficial antigens by blood monocytes and granulocytes as well as the number of leukocyte-platelet complexes forming in in vitro activation in patients subjected to coronary angioplasty; to analyse changes in these parameters in coronary restenosis. MATERIAL AND METHODS: Membrane expression of leukocytic antigens and the number of leukocyte-platelet complexes after activation in the whole blood were measured by direct immunofluorescence and flow cytometry in 24 patients who have undergone stenting of coronary arteries. 14 of them had angiographically confirmed restenosis. RESULTS: The tests discovered high expression of integrins Mac-1 and VLA-4 by monocytes and elevated relative number of monocyte-platelet complexes in patients with restenosis vs those free of stenosis (1425 +/- 76 and 1195 +/- 71 r.u. for Mac-1, 87 +/- 7 and 65 +/- 6 r.u. for VLA-4, 47 +/- 4 and 29 +/- 3%, respectively, for monocyte-platelet complexes; p < 0.05 for all the indices). CONCLUSION: Coronary restenosis may result from elevated expression of adhesion molecules by monocytes manifest in activation of the cells in vitro.
Assuntos
Plaquetas , Moléculas de Adesão Celular/sangue , Reestenose Coronária/sangue , Monócitos/metabolismo , Angioplastia Coronária com Balão , Agregação Celular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regulação para CimaRESUMO
The role of beta2-integrins CD11b/CD18 and CD 11c/CD 18 in adhesion and migration of leukocytes on fibrinogen was studied. The monoclonal antibodies against CD11b inhibited the spontaneous adhesion of monocytic THP-1 cells on fibrinogen, whereas antibodies to CD11c more effectively inhibited the adhesion stimulated by chemokine MCP-1. By the RNA-interference method the clones of THP-1 with reduced expression of CD11b and general beta2-subunit CD18 were obtained. MCP-I stimulated the adhesion to fibrinogen of THP-1 cells of wild-type and mutant cells with reduced expression of CD11b (THP-1-CD11b-low), but not of cells with low expression of CD18 (THP-1-CD18-low). THP-1-CD18-low cells were also characterized by the impaired chemotaxis in presence of MCP-1. The data obtained suggest that spontaneous cell adhesion to fibrinogen is mediated to a greater extent by CD11b/CD18 integrins, while chemokine-stimulated adhesion and migration is mostly dependent on CD11c/CD18 molecules.