RESUMO
Long non-coding RNAs (lncRNAs) participate in the modulation of cardiac hypertrophy, and they represent potential therapeutic targets in cardiovascular disease. We investigated the expression profiles of selected lncRNAs in peripheral blood mononuclear cells of patients with essential hypertension in relation to left ventricular hypertrophy. We assessed the expression levels of the lncRNAs MHRT, FENDRR and CARMEN using real-time reverse transcription polymerase chain reaction. Hypertensive patients showed significantly higher MHRT, FENDRR and CARMEN expression levels compared with healthy controls. In addition, we observed significant negative correlations of MHRT (r = -0.323, P = 0.003) and FENDRR (r = -0.380, P = 0.001) and a positive correlation of CARMEN (r = 0.458, P < 0.001) expression levels with left ventricular mass index. Our data reveal that the lncRNAs MHRT, FENDRR and CARMEN show distinct expression profiles in hypertensive patients and they possibly represent candidate therapeutic targets in hypertensive heart disease.
Assuntos
Cardiomegalia/complicações , Hipertensão Essencial/complicações , Hipertensão Essencial/genética , Regulação da Expressão Gênica , Leucócitos Mononucleares/metabolismo , RNA Longo não Codificante/genética , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
AIM: Long-term right ventricular apical (RVA) pacing may lead to left ventricular (LV) remodelling and heart failure. This study assessed changes in the expression of genes regulating LV contractile function and hypertrophy, after permanent RVA pacing and investigated whether such changes proceed or even predict LV remodelling. METHODS AND RESULTS: We enrolled 52 consecutive patients (age 79.1 ± 7.7 years, 34 males) who underwent pacemaker implantation for bradycardic indications: Group A, 24 individuals with atrioventricular conduction disturbances and group B, 28 patients with sinus node disease. In group A, peripheral blood mRNA levels of gene sarcoplasmic reticulum calcium ATPase decreased at 3, 6, and 12 months' follow-up, while α-myosin heavy chain (MHC) decreased and ß-MHC increased until 6 months follow-up. In this group, 25% of patients demonstrated significant LV remodelling. At 4 years, LV end-systolic diameter increased from 29.67 ± 3.39 mm at baseline to 35.38 ± 4.22 mm, LV end-diastolic diameter increased from 50 ± 4.95 to 56.71 ± 5.52 mm, and ejection fraction declined from 63.04 ± 10.22 to 52.83 ± 10.81%. Early alterations in gene expression were associated with a deterioration in LV function and geometry that became apparent months later. In group B, echocardiographic indexes and mRNA levels of the evaluated genes demonstrated no statistically significant changes. CONCLUSIONS: Permanent RVA pacing in patients with preserved ejection fraction is associated with alterations in the expression of genes regulating LV contractile function and hypertrophy, measured in the peripheral blood. These alterations are traceable at an early stage, before echocardiographic changes are apparent and are associated with LV remodelling that becomes evident in the long term.
Assuntos
Miosinas Cardíacas/sangue , Ventrículos do Coração/fisiopatologia , Cadeias Pesadas de Miosina/sangue , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/sangue , Síndrome do Nó Sinusal/complicações , Função Ventricular Esquerda/genética , Remodelação Ventricular/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Bradicardia/terapia , Estimulação Cardíaca Artificial/métodos , Ecocardiografia , Feminino , Insuficiência Cardíaca/terapia , Humanos , Masculino , Marca-Passo Artificial , Estudos Prospectivos , Volume SistólicoRESUMO
Cardiac muscle contraction occurs through an interaction of the myosin head with the actin filaments, a process which is regulated by the troponin complex together with tropomyosin and is Ca(2+) dependent. Mutations in genes encoding sarcomeric proteins are a common cause of familial hypertrophic and dilated cardiomyopathies. The scope of this review is to gather information from studies regarding the in vitro characterisation of six HCM and six DCM mutations on the cardiac TnC gene and to suggest, if possible, how they may lead to dysfunction. Since TnC is the subunit responsible for Ca(2+) binding, mutations in the TnC could possibly have a strong impact on Ca(2+) binding affinities. Furthermore, the interactions of mutant TnCs with their binding partners could be altered. From the characterisation studies available to date, we can conclude that the HCM mutations on TnC increase significantly the Ca(2+) sensitivity of force development or of ATPase activity, producing large pCa shifts in comparison to WT TnC. In contrast, the DCM mutations on TnC have a tendency to decrease the Ca(2+) sensitivity of force development or of ATPase activity in comparison to WT TnC. Furthermore, the DCM mutants of TnC are not responsive to the TnI phosphorylation signal resulting in filaments that preserve their Ca(2+) sensitivity in contrast to WT filaments that experience a decrease in Ca(2+) sensitivity upon TnI phosphorylation.
Assuntos
Cardiomiopatia Dilatada/metabolismo , Tropomiosina/metabolismo , Troponina C/metabolismo , Sequência de Aminoácidos , Animais , Cálcio/metabolismo , Cardiomiopatia Dilatada/genética , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Músculo Esquelético/metabolismo , Tropomiosina/química , Tropomiosina/genética , Troponina C/química , Troponina C/genéticaRESUMO
BACKGROUND: MicroRNAs (miRs) regulate gene expression and play an important role in ventricular and vascular remodeling. However, there are limited data regarding their role in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to assess gene expression of miR-1, miR-133a, miR-21, miR-208b, miR-499, and miR-26b in peripheral blood mononuclear cells (PBMCs) in hypertensive patients with HFpEF and to evaluate their association with their exercise capacity. METHODS: We included 56 hypertensive patients with HFpEF (age 67.29 ± 7.75 years). Forty-two hypertensive patients without HFpEF (age 66.83 ± 7.17 years) served as controls. All subjects underwent a cardiopulmonary exercise test (CPXT). PBMCs were isolated and levels of miRs were determined by quantitative real-time reverse transcription polymerase chain reaction. RESULTS: For hypertensive patients with HFpEF, higher expression levels in PBMCs were found only for miR-26b (7.6 ± 7.3 vs. 4.0 ± 3.6, P = 0.002), miR-208b (28.8 ± 35.3 vs. 7.5 ± 13.3, P < 0.001), and miR-499 (14.2 ± 22.4 versus 3.5 ± 2.9, P = 0.001). The strongest correlations with CPXT parameters were found for miR-208b levels, which had a positive correlation with maximal oxygen uptake (peakVO2) (r = 0.671, P < 0.001), exercise duration (r = 0.445, P = 0.001), and minute ventilation-carbon dioxide production relationship (VE/VCO2) (r = 0.437, P = 0.001) in the HFpEF group. CONCLUSIONS: miR-26b, miR-208b, and miR-499 show a distinct in profile in hypertensive patients with HFpEF that is related with functional capacity. Further studies are needed to assess the role of miRs as prognostic tools or as therapeutic targets in those patients.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Hipertensão/fisiopatologia , Leucócitos Mononucleares/química , MicroRNAs/fisiologia , Volume Sistólico/fisiologia , Idoso , Biomarcadores , Teste de Esforço , Feminino , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Consumo de OxigênioRESUMO
BACKGROUND: Early cardiac marker genes, such as cardiac-specific homeobox (Csx/Nkx2.5), myocardin, homeodomain only protein, GATA4, and myocyte enhancer factor 2C, are thought to participate in cardiomyocyte differentiation and to contribute to heart hypertrophy in animal models. In this study, we investigated whether the expression of early cardiac genes is altered in the peripheral blood of patients with hypertrophic cardiomyopathy. METHODS: Peripheral blood mononuclear cells were isolated from 30 consecutive hypertrophic cardiomyopathy patients and 20 healthy controls, and gene expression was determined by quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: Csx/Nkx2.5, myocardin, and GATA4 expressions were significantly higher in hypertrophic cardiomyopathy patients by 5.14+/-0.89 (P<.001), 1.65+/-0.21 (P<.05), and 2.04+/-0.41 (P<.04) times, respectively, while homeodomain only protein showed a fourfold decrease in expression (P<.02) compared to controls. In addition, expression of the differentiation-specific marker genes beta-myosin heavy chain and smooth muscle myosin heavy chain was significantly higher in hypertrophic cardiomyopathy patients by 3.72+/-0.82 (P<.02) and 2.57+/-0.72 (P<.05) times, respectively, compared to controls. Myocyte enhancer factor 2C expression was not different between patients and controls. Furthermore, increased expression of GATA4, myocardin, and beta-myosin heavy chain positively correlated with increased left ventricular mass. CONCLUSIONS: In conclusion, we found altered expressions of early cardiac marker genes and differentiation-specific marker genes in peripheral blood mononuclear cells of hypertrophic cardiomyopathy patients compared to control individuals, possibly reflecting changes in response to disease.
Assuntos
Cardiomiopatia Hipertrófica/genética , Regulação da Expressão Gênica , Leucócitos Mononucleares/química , Adulto , Idoso , Biomarcadores/sangue , Cardiomiopatia Hipertrófica/sangue , Cardiomiopatia Hipertrófica/patologia , Estudos de Casos e Controles , Feminino , Fator de Transcrição GATA4/sangue , Fator de Transcrição GATA4/genética , Ventrículos do Coração/patologia , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/sangue , Proteínas de Homeodomínio/genética , Humanos , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Leucócitos Mononucleares/patologia , Proteínas de Domínio MADS/sangue , Proteínas de Domínio MADS/genética , Fatores de Transcrição MEF2 , Masculino , Pessoa de Meia-Idade , Fatores de Regulação Miogênica/sangue , Fatores de Regulação Miogênica/genética , Cadeias Pesadas de Miosina/sangue , Cadeias Pesadas de Miosina/genética , Proteínas Nucleares/sangue , Proteínas Nucleares/genética , RNA Mensageiro/sangue , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores/sangue , Transativadores/genética , Fatores de Transcrição/sangue , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/sangue , Proteínas Supressoras de Tumor/genéticaRESUMO
Catecholamines play a major role in atherothrombotic mechanisms in essential hypertension. Alpha2B-adrenergic receptors (α2B-ARs) are implicated in the pathophysiology of platelet aggregation. In this study, we evaluated platelet α2B-AR gene expression levels in patients with well-controlled essential hypertension compared with normal individuals and investigated their association with increased arterial stiffness. Fifty-nine patients with well-controlled essential hypertension (34 men, mean age 65 ± 9 years) and 26 normotensives (19 men, mean age 64 ± 8 years) were included in the study. For each patient, carotid-femoral pulse wave velocity (PWV) and carotid-radial PWV were evaluated. In addition, blood samples were obtained and platelets were isolated. The α2B-AR gene expression levels in platelets were examined by real-time polymerase chain reaction for each participant. Well-controlled hypertensive patients showed significantly higher gene expression levels of α2B-Rs in platelets compared with normotensives (34.7 ± 29.5 vs 17.6 ± 12.5, respectively, P = .005). Interestingly, we found that carotid-femoral PWV and carotid-radial PWV were positively correlated with platelet α2B-R gene expression levels (r = 0.59, P < .001, and r = 0.39, P = .002, respectively).Platelet α2B-R gene expression levels are increased in patients with well-controlled essential hypertension compared with normotensives and are correlated with increased PWV in those patients. Our data indicate an association of arterial stiffness and platelet α2B-Rs gene expression and indicate the need for further research.
Assuntos
Plaquetas/metabolismo , Hipertensão Essencial/fisiopatologia , Receptores Adrenérgicos alfa 2/metabolismo , Rigidez Vascular/fisiologia , Idoso , Pressão Sanguínea/fisiologia , Artérias Carótidas/fisiopatologia , Hipertensão Essencial/tratamento farmacológico , Feminino , Artéria Femoral/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso , Artéria Radial/fisiopatologia , Reação em Cadeia da Polimerase em Tempo RealRESUMO
AIMS: Endothelial progenitor cells (EPCs) are bone marrow-derived cells that are mobilized into the circulation to migrate and differentiate into mature endothelial cells contributing to post-natal physiological and pathological neovascularization. In this study, we evaluated circulating EPCs in patients with hypertrophic cardiomyopathy (HCM) and examined a potential association with clinical parameters of the disease. METHODS AND RESULTS: We included 40 HCM patients and 23 healthy individuals. Using flow cytometry we measured EPCs in peripheral blood as two subpopulations of CD45-/CD34+/VEGFR2+ and CD45-/CD34+/CD133+ cells. Circulating CD45-/CD34+/VEGFR2+ cells were significantly increased in HCM patients in comparison with the controls (0.000238 ± 0.0003136 vs. 0.000057 ± 0.0001316, respectively, P = 0.002). However, there was no significant difference in the number of circulating CD45-/CD34+/CD133+ cells (0.003079 ± 0.0033288 vs. 0.002065 ± 0.0022173, respectively, P = 0.153). The CD45-/CD34+/VEGFR2+ subpopulation revealed a moderate correlation with LV mass index (r = 0.35, P = 0.026), while both EPC subpopulation levels showed strong positive correlations with th E/e' ratio (r = 0.423, P = 0.007 for CD45-/CD34+/VEGFR2+ and r = 0.572, P < 0.001 for CD45-/CD34+/CD133+). CONCLUSION: HCM patients showed an increased mobilization of EPCs compared with healthy individuals that correlated with diastolic dysfunction. Our findings may open up new dimensions in the pathophysiology, prognostication, and treatment of HCM.
Assuntos
Cardiomiopatia Hipertrófica/fisiopatologia , Células Progenitoras Endoteliais/fisiologia , Adulto , Idoso , Biomarcadores/sangue , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/tratamento farmacológico , Células Progenitoras Endoteliais/citologia , Células Progenitoras Endoteliais/patologia , Feminino , Citometria de Fluxo , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , UltrassonografiaRESUMO
MicroRNAs regulate several aspects of physiological and pathologic cardiac hypertrophy, and they represent promising therapeutic targets in cardiovascular disease. We assessed the expression levels of the microRNAs miR-1, miR-133a, miR-26b, miR-208b, miR-499, and miR-21, in 102 patients with essential hypertension and 30 healthy individuals. All patients underwent two-dimensional echocardiography. MicroRNA expression levels in peripheral blood mononuclear cells were quantified by real-time reverse transcription polymerase chain reaction. Hypertensive patients showed significantly lower miR-133a (5.06 ± 0.50 vs. 13.20 ± 2.15, P < .001) and miR-26b (6.76 ± 0.53 vs. 9.36 ± 1.40, P = .037) and higher miR-1 (25.99 ± 3.07 vs. 12.28 ± 2.06, P = .019), miR-208b (22.29 ± 2.96 vs. 8.73 ± 1.59, P = .016), miR-499 (10.06 ± 1.05 vs. 5.70 ± 0.91, P = .033), and miR-21 (2.75 ± 0.15 vs. 1.82 ± 0.20, P = .002) expression levels compared with healthy controls. In hypertensive patients, we observed significant negative correlations of miR-1 (r = -0.374, P < .001) and miR-133a (r = -0.431, P < .001) and significant positive correlations of miR-26b (r = 0.302, P = .002), miR-208b (r = 0.426, P < .001), miR-499 (r = 0.433, P < .001) and miR-21 (r = 0.498, P < .001) expression levels with left ventricular mass index. Our data reveal that miR-1, miR-133a, miR-26b, miR-208b, miR-499, and miR-21 show distinct expression profiles in hypertensive patients relative to healthy individuals and they are associated with clinical indices of left ventricular hypertrophy in hypertensive patients. Thus, they may be related to heart hypertrophy in hypertensive patients and are possibly candidate therapeutic targets in hypertensive heart disease.
Assuntos
Perfilação da Expressão Gênica , Hipertensão/sangue , Hipertrofia Ventricular Esquerda/sangue , MicroRNAs/sangue , Idoso , Biomarcadores/sangue , Hipertensão Essencial , Feminino , Humanos , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/etiologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , UltrassonografiaRESUMO
BACKGROUND: This study examines the mobilization of mesenchymal stem cells (MSCs) in patients with hypertrophic cardiomyopathy (HCM) compared to healthy individuals. The pathogenesis of myocardial hypertrophy in HCM is not fully understood. MSCs are involved in the process of neovascularization, fibrosis, and ventricular wall remodeling. METHODS AND RESULTS: We included 40 patients with HCM and 23 healthy individuals. Using flow cytometry, we measured MSCs in peripheral blood, as a population of CD45-/CD34-/CD90+ cells and also as a population of CD45-/CD34-/CD105+ cells. The resulting MSC counts were expressed as percentages of the total cells. Patients with HCM were found to have a greater percentage of circulating CD45-/CD34-CD34-/CD90+ cells compared to controls (0.0041±0.005% vs. 0.0007±0.001%, respectively, P<.001). No significant difference in circulating CD45-/CD34-/CD105+ cells in the peripheral blood was found between HCM patients and controls (0.016±0.018% vs. 0.012±0.014%, respectively, P=.4). Notably, circulating CD45-/CD34-/CD90+ cells were positively correlated with left ventricular mass index (r=0.54, P<.001). CONCLUSIONS: Patients with HCM reveal an increased mobilization of MSCs compared to healthy individuals. Although further research is needed to reveal the clinical significance of our findings, our data open a new dimension in the pathophysiology of the disease and may indicate new future therapeutic possibilities.
Assuntos
Cardiomiopatia Hipertrófica/sangue , Cardiomiopatia Hipertrófica/patologia , Células-Tronco Mesenquimais , Idoso , Antígenos CD/análise , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
MicroRNAs (miRs), as essential gene expression regulators, modulate cardiovascular development and disease and thus they are emerging as potential biomarkers and therapeutic targets in cardiovascular disease, including hypertension. We assessed the expression levels of the microRNAs miR-9 and miR-126 in 60 patients with untreated essential hypertension and 29 healthy individuals. All patients underwent two-dimensional echocardiography and 24-hour ambulatory blood pressure monitoring. MicroRNA expression levels in peripheral blood mononuclear cells were quantified by real-time reverse transcription polymerase chain reaction. Hypertensive patients showed significantly lower miR-9 (9.69 ± 1.56 vs 41.08 ± 6.06; P < .001) and miR-126 (3.88 ± 0.47 vs 8.96 ± 1.69; P < .001) expression levels compared with healthy controls. In hypertensive patients, miR-9 expression levels showed a significant positive correlation (r = 0.437; P < .001) with left ventricular mass index. Furthermore, both miR-9 (r = 0.312; P = .015) and miR-126 (r = 0.441; P < .001) expression levels in hypertensive patients showed significant positive correlations with the 24-hour mean pulse pressure. Our data reveal that miR-9 and miR-126 are closely related to essential hypertension in humans, as they show a distinct expression profile in hypertensive patients relative to healthy individuals, and they are associated with clinical prognostic indices of hypertensive target-organ damage in hypertensive patients. Thus, they may possibly represent potential biomarkers and candidate therapeutic targets in essential hypertension.
Assuntos
Pressão Sanguínea/fisiologia , Regulação da Expressão Gênica , Hipertensão/genética , MicroRNAs/genética , RNA/genética , Hipertensão Essencial , Feminino , Seguimentos , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , MicroRNAs/biossíntese , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo RealRESUMO
INTRODUCTION: The early cardiac marker genes myocardin, GATA4 and Nkx2.5, play a role in both embryonic cardiovascular development and adult cardiovascular disease. We evaluated transcript levels of myocardin, GATA4 and Nkx2.5 in peripheral blood mononuclear cells (PBMCs) in patients with stable coronary artery disease (CAD) and we examined the relationship between these levels and the severity of the disease, estimated by the number of stenotic vessels involved. METHODS: Ninety-eight patients with stable CAD (age 66 ± 9 years) who underwent coronary angiography participated in the study; 66 healthy individuals (age 58 ± 13 years) were also included for comparison. Gene transcript levels were determined by quantitative real-time reverse transcription polymerase chain reaction. RESULTS: Patients with 3-vessel CAD had elevated transcript levels of myocardin (median difference 2.7, p=0.001, 95% confidence interval, CI: 1-5.8), GATA4 (median difference 0.3, p=0.015, 95% CI: 0.1-1.9) and Nkx2.5 (median difference 16.1, p<0.001, 95% CI: 4.5-23) compared to healthy controls. Patients with 3-vessel CAD also showed elevated transcript levels of myocardin (median difference 2.3, p=0.001, 95% CI: 0.49-5.5) and Nkx2.5 (median difference 11.8, p<0.001, 95% CI: 1.5-21.5) compared to patients with 1-vessel CAD. CONCLUSIONS: Early cardiac marker gene transcript levels are significantly higher in the PBMCs of patients with severe stable CAD than in those of healthy controls, and show alterations in their expression profile according to the disease severity status. Our results indicate for the first time that changes in the early cardiac gene expression in the peripheral blood of stable CAD patients, possibly as a result of alterations in circulating cardiovascular progenitor cells that express these genes, may reflect the level of disease severity.
Assuntos
Doença da Artéria Coronariana , Fator de Transcrição GATA4/genética , Proteínas de Homeodomínio/genética , Leucócitos Mononucleares , Proteínas Nucleares/genética , Transativadores/genética , Fatores de Transcrição/genética , Idoso , Biomarcadores/sangue , Intervalos de Confiança , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Feminino , Perfilação da Expressão Gênica , Proteína Homeobox Nkx-2.5 , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Transcrição GênicaRESUMO
Stem cells have great clinical significance in many cardiovascular diseases. However, there are limited data regarding the involvement of mesenchymal stem cells (MSCs) in the pathophysiology of arterial hypertension. The aim of this study was to investigate the circulation of MSCs in patients with essential hypertension. The authors included 24 patients with untreated essential hypertension and 19 healthy individuals. Using flow cytometry, MSCs in peripheral blood, as a population of CD45-/CD34-/CD90+ cells and also as a population of CD45-/CD34-/CD105+ cells, were measured. The resulting counts were translated into the percentage of MSCs in the total cells. Hypertensive patients were shown to have increased circulating CD45-/CD34-/CD90+ compared with controls (0.0069%±0.012% compared with 0.00085%±0.0015%, respectively; P=.039). No significant difference in circulating CD45-/CD34-/CD105+ cells was found between hypertensive patients' and normotensive patients' peripheral blood (0.018%±0.013% compared with 0.015%±0.014%, respectively; P=.53). Notably, CD45-/CD34-/CD90+ circulating cells were positively correlated with left ventricular mass index (LVMI) (r=0.516, P<.001). Patients with essential hypertension have increased circulating MSCs compared with normotensive patients, and the number of MSCs is correlated with LVMI. These findings contribute to the understanding of the pathophysiology of hypertension and might suggest a future therapeutic target.
Assuntos
Hipertensão/sangue , Hipertrofia Ventricular Esquerda/fisiopatologia , Células-Tronco Mesenquimais/citologia , Idoso , Ecocardiografia , Hipertensão Essencial , Feminino , Citometria de Fluxo , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
The potential association between arterial stiffening and circulating endothelial progenitor cells (EPCs) in patients with essential hypertension was investigated. Pulse wave velocity (PWV) was used to evaluate arterial stiffness in 24 patients with essential hypertension and 19 healthy controls. Blood samples were taken and immunostained with antibodies against the cell surface markers CD34, CD45, and CD133. Using flow cytometry, EPCs as a population of CD45-/CD34+/CD133+ cells were measured. Hypertensive patients were not found to have higher levels of circulating CD45-/CD34+/CD133+ compared with the control group (0.0026%±0.0031% vs 0.0023%±0.0023%, respectively; P=.7). Correlation analysis revealed a strong association between the number of CD45-/CD34+/CD133+ cells and PWV (r=0.58, P<.001), indicating that hypertensive patients with increased PWV have a greater percentage of CD45-/CD34+/CD133+ cells. Data showed a correlation between the number of circulating CD45-/CD34+/CD133+ cells and arterial stiffness, suggesting that those cells might have a role in arterial remodeling.
Assuntos
Células Progenitoras Endoteliais/imunologia , Hipertensão/sangue , Hipertensão/fisiopatologia , Rigidez Vascular/fisiologia , Antígeno AC133 , Idoso , Antígenos CD/metabolismo , Antígenos CD34/metabolismo , Estudos de Casos e Controles , Células Progenitoras Endoteliais/patologia , Células Progenitoras Endoteliais/fisiologia , Hipertensão Essencial , Feminino , Glicoproteínas/metabolismo , Humanos , Antígenos Comuns de Leucócito/metabolismo , Masculino , Pessoa de Meia-Idade , Peptídeos/metabolismo , Estudos Prospectivos , Análise de Onda de Pulso , Remodelação Vascular/fisiologiaRESUMO
The activation of innate immune receptors, such as Toll-like receptors (TLRs), participates in the pathogenesis of cardiovascular diseases. The authors evaluated TLR2 and TLR4 gene expression in the peripheral monocytes of nondiabetic hypertensive patients compared with normotensive individuals and investigated the effect of intensive systolic blood pressure (SBP)-lowering. Included were 43 nondiabetic hypertensive patients with essential hypertension who were randomly assigned to an intensive treatment arm, with an SBP target of <130 mm Hg, or a standard arm, with an SBP target of <140 mm Hg. TLR2 and TLR4 messenger RNA (mRNA) levels in monocytes were estimated before and 12 weeks after therapy initiation. Sixteen healthy individuals were included for comparison. Hypertensives revealed significantly higher TLR4 mRNA levels compared with normotensives (985 ± 885 vs 554 ± 234, P=.005). In contrast, no statistically significant difference was found in TLR2. Compared with standard treatment, intensive treatment significantly downregulated TLR2 and TLR4 mRNAs, expressed as fold induction (0.66 ± 0.49 vs 1.38 ± 1.65 and 0.62 ± 0.3 vs 1.9 ± 1.2, respectively; P<.001 for both). In conclusion, TLR4 mRNA levels in peripheral monocytes are significantly elevated in nondiabetic hypertensive patients. Intensive control of SBP results in attenuation of TLR2 and TLR4 gene expression in those patients. Our findings suggest that a strict SBP target in nondiabetic hypertensive patients may offer additional benefits.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Leucócitos Mononucleares/metabolismo , Receptor 2 Toll-Like/sangue , Receptor 4 Toll-Like/sangue , Adulto , Idoso , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Estudos de Casos e Controles , Regulação para Baixo/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Mensageiro/sangue , Resultado do TratamentoRESUMO
OBJECTIVES: To assess the expression of early cardiac genes, implicated in the hypertrophic growth response of the adult heart, in peripheral blood mononuclear cells in patients with essential hypertension and its relationship to ambulatory blood pressure monitoring (ABPM) parameters and to echocardiographic left ventricular mass. METHODS: Twenty-four-hour ABPM, echocardiography and blood sampling were performed in 62 untreated participants with essential hypertension. Blood samples from 38 healthy individuals were included for comparison. Peripheral blood mononuclear cells (PBMCs) were isolated and gene transcript levels were determined by quantitative real-time reverse transcription PCR. RESULTS: Myocardin (3.92±0.68 versus 2.09±0.67, P<0.001), GATA4 (3.48±0.68 versus 0.32±0.08, P<0.001) and Nkx2.5 (208.91±35.01 versus 129.75±49.70, P<0.001) were upregulated in hypertensive patients compared with controls. In hypertensive patients, transcript levels of myocardin (r=0.698, P<0.001) and GATA4 (r=0.374, P=0.003) showed significant positive correlations with 24-h systolic blood pressure (BP) as well as with mean BP, (r=0.626, P<0.001) and (r=0.340, P=0.007), respectively. A significant positive correlation between myocardin and 24-h pulse pressure (r=0.467, P<0.001) was also observed. Myocardin (r=-0.606, P<0.001) and GATA4 (r=-0.453, P<0.001) transcript levels also showed significant negative correlations with the mean 24-h dipping status. Additionally, myocardin (r=0.341, P=0.007), GATA4 (r=0.337, P=0.007) and Nkx2.5 (r=0.325, P=0.010) transcript levels showed significant positive correlations with left ventricular mass index. CONCLUSION: Myocardin and GATA4 transcript levels correlate significantly with 24-h ABPM parameters, rendering them potential candidate biomarkers in hypertension. Early cardiac gene transcript levels in PBMCs of hypertensive patients are associated with left ventricular mass and may reflect activation of the hypertrophic response gene network in these patients.
Assuntos
Hipertensão/metabolismo , Monócitos/metabolismo , RNA Mensageiro/metabolismo , Idoso , Feminino , Humanos , Hipertensão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , UltrassonografiaRESUMO
Monocyte chemoattractant protein-1 (MCP-1) and peroxisome proliferator-activated receptor-γ (PPAR-γ) play a significant role in monocyte activation, vascular inflammation, and atherogenesis. Angiotensin receptor blockers and calcium channel blockers are antihypertensive drugs with established efficacy and a favorable safety profile. We investigated the effect of telmisartan--an angiotensin receptor blocker with PPAR-γ agonist activity--and amlodipine on the activation state of peripheral blood monocytes with respect to MCP-1 and PPAR-γ gene expression in hypertensives. We recruited 31 previously untreated patients with essential hypertension who were randomly assigned to receive treatment with telmisartan (n = 16) or amlodipine (n = 15). Blood samples were taken before and 3 months after therapy initiation. Mononuclear cells were isolated and mRNAs of MCP-1 and PPAR-γ were estimated by real-time quantitative reverse transcription-polymerase chain reaction each time. The 2 treatments decreased all blood pressure components significantly (p <0.001). In contrast, in the amlodipine group, MCP-1 gene expression was significantly downregulated after treatment with telmisartan (from 21.4 ± 20.5 to 8.1 ± 6.5, p = 0.009), whereas the amlodipine group did not show any significant change (12.5 ± 8.5 vs 17.6 ± 16.4, p = NS). In addition, PPAR-γ mRNA levels showed a significant increase in telmisartan-treated patients (from 20 ± 18.5 to 42.6 ± 36, p = 0.006) and no significant alterations in the amlodipine group (from 29.6 ± 42.5 to 24.2 ± 27.7, p = NS). In conclusion, treatment with telmisartan results in a significant attenuation of MCP-1 gene expression and an increase of PPAR-γ gene expression in peripheral monocytes in patients with essential hypertension. Our findings may provide new insights into the cardiovascular protection of telmisartan in hypertensives.
Assuntos
Anlodipino/farmacologia , Anti-Hipertensivos/farmacologia , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Quimiocina CCL2/genética , Hipertensão/tratamento farmacológico , Monócitos/efeitos dos fármacos , PPAR gama/genética , Anlodipino/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Benzimidazóis/uso terapêutico , Benzoatos/uso terapêutico , Quimiocina CCL2/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , TelmisartanRESUMO
AIMS: To assess cardiac gene expression in peripheral blood cells of patients with idiopathic dilated cardiomyopathy (IDCM) and its relationship to echocardiographic left ventricular (LV) function. METHODS AND RESULTS: A complete echocardiographic study and blood sampling were performed in 65 consecutive stable IDCM patients with LV ejection fraction (LVEF) 31.76 +/- 10.07% and chronic mild to moderate heart failure (NYHA functional class II to III) for > or =9 months. Blood samples from 19 healthy individuals were included for comparison. Transcript levels of myocardin, GATA4, alpha- and beta-myosin heavy chain (MHC), sarcoplasmic reticulum calcium ATPase 2 (SERCA2), and phospholamban were determined by quantitative real-time reverse transcription-polymerase chain reaction. Myocardin (24.88 +/- 4.93 vs. 3.98 +/- 1.12, P = 0.0048) and GATA4 (17.85 +/- 4.85 vs. 0.45 +/- 0.15, P = 0.0069 x 10(-5)) were upregulated in IDCM patients compared with controls, whereas SERCA2 (5.11 +/- 0.42 vs. 8.93 +/- 1.07, P = 0.001) was downregulated. In IDCM patients, myocardin (r = 0.279, P = 0.025), GATA4 (r = 0.314, P = 0.011), beta-MHC (r = 0.444, P=0.0002), and alpha-MHC (r = 0.272, P = 0.034) showed positive correlations, whereas SERCA2 (r = -0.264, P = 0.034) exhibited a negative correlation with LVEF. Patients with elevated LV filling pressures had lower myocardin (15.06 +/- 3.10 vs. 43.12 +/- 12.03, P = 0.048), GATA4 (8.96 +/- 2.17 vs. 34.38 +/- 12.60, P = 0.026), beta-MHC (10.59 +/- 4.05 vs. 16.43 +/- 4.91, P = 0.013), and alpha-MHC (0.27 +/- 0.08 vs. 0.79 +/- 0.20, P = 0.033) and higher SERCA2 (5.65 +/- 0.54 vs. 3.90 +/- 0.61, P = 0.037) levels. Patients with atrial fibrillation (AF) had higher SERCA2 levels compared with sinus rhythm patients (6.75 +/- 0.84 vs. 4.54 +/- 0.45, P = 0.017). CONCLUSION: Our data indicate that cardiac gene expression alterations in peripheral blood cells of IDCM patients may reflect alterations in LV function, whereas the presence of AF may be associated with increased SERCA2 levels in these patients.