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1.
Biochim Biophys Acta Mol Basis Dis ; 1866(3): 165627, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31785407

RESUMO

Macrophages play an important role in aldosterone-induced myocardial fibrosis, in which the first key steps are macrophage recruitment and infiltration. We hypothesized that IL-6 may be a key mediator of aldosterone-induced macrophage recruitment and infiltration. To test this hypothesis, we designed cell studies with a human monocytic cell line THP-1 that with monocyte/macrophage functions to explore the signaling pathway of aldosterone-induced macrophage infiltration, and further investigated the phenomenon and consequent pathway in aldosterone-infused mice studies. The results showed that aldosterone induced the expression of IL-6 via mineralocorticoid receptors, and enhanced THP-1 cell migration and infiltration. Further experiments using a protease array and siRNA revealed that expressions of MMP-1 and MMP-9 were associated with aldosterone-induced macrophage infiltration. In addition, aldosterone-induced MMP-1 and MMP-9 expressions were mediated via cyclooxygenase-II and prostaglandin E2/EP-2 and EP-4 receptors. In aldosterone-infused mice, mRNA expressions of MMP-1, MMP-9 and COX-2 in peripheral blood monocytic cells were significantly increased. Moreover, the number of mouse macrophage-restricted F4/80 protein-positive cells in the myocardium was significantly higher in the aldosterone-infused mice compared with control mice. The increase in F4/80-positive cells in the myocardium was suppressed in the aldosterone-infused mice with the aldosterone antagonist eplerenone or anti-IL-6 antibody treatment. In conclusion, interleukin-6 played an important role in aldosterone-induced macrophage recruitment and infiltration in the myocardium.

2.
J Investig Med ; 68(2): 371-377, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31630138

RESUMO

Estimated glomerular filtration rate (eGFR) is an important topic in patients with primary aldosteronism (PA). However, the relationship between left ventricular structure and eGFR is unclear. We conducted a prospective, observational, and cross-sectional study to analyze 168 patients with PA and 168 propensity score-matched patients with essential hypertension (EH) as the control group, matched by age, gender, and systolic blood pressure. In the patients with PA, the eGFR was not correlated with left ventricular mass index (LVMI; r=-0.065, p=0.404), while in the patients with EH, the eGFR was negatively correlated with LVMI (r=-0.309, p<0.001). To test whether eGFR had a non-linear relationship with LVMI among the patients with PA, we stratified the patients with PA according to the tertile of eGFR (low, medium, and high tertile). The medium tertile of patients had a significantly lower LVMI than those in the other two tertiles (LVMI: 143.5±41.6, 120.5±40.5, and 133.1±34.3 g/m2, from the lowest to highest tertile of eGFR; analysis of covariance p=0.032). The medium tertile of eGFR is associated with lowest LVMI. Patients with PA with high and low eGFR were associated with higher LVMI. The findings implied that the reasons for an increased LVMI in patients with PA may be different to those in patients with EH.

3.
World J Microbiol Biotechnol ; 35(12): 180, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31728755

RESUMO

Derived from RNA, 5'-ribonucleotides, especially Inosine-5'-monophosphate (IMP) and guanosine-5'-monophosphate (GMP), can enhance the umami taste of soy sauce. In this study, the RNA content of three different salt-tolerant yeasts was examined. The most valuable strain was subjected to atmospheric and room-temperature plasma (ARTP) mutagenesis, which improved its RNA content by 160.54%. Regular fermentation with RNA-enhanced strain failed to increase the amount of 5'-ribonucleotides in the soy sauce due to hydrolysis by phosphatase. A two-stage fermentation strategy was then carried out. Aroma compounds were mainly synthesized in the first stage, and RNA-enriched biomass was massively produced in the second stage followed by heat treatment to inactivate phosphatase. After the proposed strategy was applied, IMP and GMP in the soy sauce reached 68.54 and 89.37 mg/L, respectively. Moreover, the amounts of key aroma compounds and organic acids significantly increased. Results may provide new insights for improving the quality of soy sauce through microorganism breeding and fermentation control.


Assuntos
Mutagênese , Gases em Plasma , RNA , Tolerância ao Sal/genética , Tolerância ao Sal/efeitos da radiação , Alimentos de Soja , Zygosaccharomyces/genética , Zygosaccharomyces/efeitos da radiação , Cruzamento , Fermentação , Microbiologia de Alimentos , Cloreto de Sódio , Paladar , Temperatura Ambiente , Zygosaccharomyces/fisiologia
4.
Nat Prod Rep ; 36(5): 788-809, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-30534698

RESUMO

Covering: 2000 to 2018 (October) Trillions of microbes, collectively termed as gut microbiota, reside in the gastrointestinal tract and are involved in the physiology of their hosts. In humans, disease incidence and medical therapy are found to be associated with gut microbiota composition. Since ethnomedicines are largely plant-derived and orally ingested, this review summarizes the interactions of gut microbiota with ethnomedicine constituents (overwhelmingly, natural phytochemicals) to highlight the knowledge accumulation in (1) the modulation of the gut microbiota profile by ingested natural compounds, and (2) the gut microbial conversion of natural products into the 'daughter molecules' with potent bioactivities. By understanding such complex interactions of gut microbiota with ethnomedicines and/or the phytochemicals thereof, a fascinating frontier of natural-product chemistry may be substantially activated to conceptualize future therapeutic strategies.


Assuntos
Produtos Biológicos/farmacologia , Disbiose/complicações , Microbioma Gastrointestinal/fisiologia , Medicina Tradicional , Plantas Medicinais/química , Doença de Alzheimer/microbiologia , Animais , Produtos Biológicos/farmacocinética , Disbiose/etiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/microbiologia , Obesidade/tratamento farmacológico , Obesidade/microbiologia , Compostos Fitoquímicos/farmacologia
5.
BMJ Open ; 8(3): e020019, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29511018

RESUMO

INTRODUCTION: Provisional stenting (PS) for simple coronary bifurcation lesions is the mainstay of treatment. A systematic two-stent approach is widely used for complex bifurcation lesions (CBLs). However, a randomised comparison of PS and two-stent techniques for CBLs has never been studied. Accordingly, the present study is designed to elucidate the benefits of two-stent treatment over PS in patients with CBLs. METHODS AND ANALYSIS: This DEFINITION II study is a prospective, multinational, randomised, endpoint-driven trial to compare the benefits of the two-stent technique with PS for CBLs. A total of 660 patients with CBLs will be randomised in a 1:1 fashion to receive either PS or the two-stent technique. The primary endpoint is the rate of 12-month target lesion failure defined as the composite of cardiac death, target vessel myocardial infarction (MI) and clinically driven target lesion revascularisation. The major secondary endpoints include all causes of death, MI, target vessel revascularisation, in-stent restenosis, stroke and each individual component of the primary endpoints. The safety endpoint is the occurrence of definite or probable stent thrombosis. ETHICS AND DISSEMINATION: The study protocol and informed consent have been approved by the Institutional Review Board of Nanjing First Hospital, and accepted by each participating centre. Written informed consent was obtained from all enrolled patients. Findings of the study will be published in a peer-reviewed journal and disseminated at conferences. TRIAL REGISTRATION NUMBER: NCT02284750; Pre-results.


Assuntos
Angioplastia Coronária com Balão/métodos , Doença da Artéria Coronariana/cirurgia , Estenose Coronária/terapia , Vasos Coronários/cirurgia , Stents , Idoso , Doença da Artéria Coronariana/patologia , Vasos Coronários/patologia , Stents Farmacológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/prevenção & controle , Intervenção Coronária Percutânea/métodos , Estudos Prospectivos , Desenho de Prótese , Projetos de Pesquisa , Resultado do Tratamento
6.
J Mol Graph Model ; 80: 211-216, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29414040

RESUMO

Olmesartan (OL) is the pharmacologically active metabolite of Olmesartan medoxomil (OM), an FDA-approved angiotensin II receptor antagonist for administrating cardiovascular diseases. The drug has been found to have potential effects on diverse protein kinase signaling involved in the pathogenesis of atherosclerosis, either by directly inhibiting the hub kinases or by indirectly modulating marginal members in the signaling pathways. In the present study, we computationally model the kinase-chemical Interaction Profile between six OL-related chemicals (i.e. OL, OM, Valsartan [VL], Losartan [LS], Candesartan [CD] and Telmisartan [TL]) and 23 human protein kinases in atherosclerosis. The profile is analyzed systematically at molecular level to identify unexpected kinase targets for OL. There is a good consistence between co-citation frequency and affinity scoring for the chemical association with kinase candidates; the OL and its analogs VL and LS exhibit a similar binding profile to the atherosclerosis kinase spectrum. It is suggested that the Ser/Thr-specific kinases PI3Kα and ROCK1 are potential druggable targets of OL for atherosclerosis therapy. As a paradigm, kinase assays reveal that the inhibitory potency of OL and Y-27632 (positive control) on ROCK1 is determined at micromolar level, while the OM (negative control) possesses no detectable activity for the kinase.


Assuntos
Imidazóis/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Proteínas Quinases/química , Tetrazóis/química , Aterosclerose/tratamento farmacológico , Aterosclerose/etiologia , Aterosclerose/metabolismo , Ativação Enzimática , Imidazóis/farmacologia , Conformação Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Tetrazóis/farmacologia
7.
Cardiovasc Res ; 114(5): 690-702, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29360942

RESUMO

Aims: An excess of aldosterone results in cardiac remodelling and fibrosis. Interleukin-6 (IL-6) is a key mediator in the fibrotic process; however, the effect of aldosterone on the expression of IL-6 remains unclear. We investigated whether aldosterone induces the expression of IL-6 and thereby contributes to the fibrotic process. Methods and results: In this clinical study, we prospectively enrolled 25 patients with primary aldosteronism (PA) and 26 patients with essential hypertension (EH). The PA patients had higher plasma IL-6 levels, left ventricular mass index, degree of myocardial fibrosis, and more impaired diastolic function than the EH patients. In addition, plasma IL-6 levels were positively correlated with 24-h urinary aldosterone and echocardiographic parameters. In cell studies, we investigated the possible molecular mechanism how aldosterone-induced IL-6 secretion and the further effects of collagen production. Aldosterone significantly induced IL-6 protein and mRNA production in human umbilical vein endothelial cells. Intracellular signalling occurred through the mineralocorticoid receptor/PI3K/Akt/NF-kB pathway. In cardiac fibroblasts, IL-6 trans-signalling played a critical role in aldosterone-induced IL-6-enhanced fibrosis-related factor expression. To further investigate the role of IL-6 trans-signalling in aldosterone-induced cardiac fibrosis, we measured the severity of myocardial fibrosis in aldosterone infusion mice models including an IL-6 chemical inhibitor and Sgp130 Knockin Transgenic Mice. Mice receiving recombinant soluble gp130 and Sgp130 Knockin Transgenic Mice prevented myocardial fibrosis and cardiac hypertrophy by aldosterone infusion. Conclusions: IL-6 trans-signalling contributes to aldosterone-induced cardiac fibrosis.


Assuntos
Aldosterona/metabolismo , Cardiomegalia/metabolismo , Fibroblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Hiperaldosteronismo/metabolismo , Interleucina-6/metabolismo , Miocárdio/metabolismo , Remodelação Ventricular , Adulto , Aldosterona/farmacologia , Animais , Cardiomegalia/etiologia , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Estudos de Casos e Controles , Células Cultivadas , Colágeno/metabolismo , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/metabolismo , Hipertensão Essencial/etiologia , Hipertensão Essencial/patologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibrose , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Hiperaldosteronismo/complicações , Interleucina-6/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Miocárdio/patologia , Estudos Prospectivos , Receptores de Mineralocorticoides/metabolismo , Transdução de Sinais
8.
Oncotarget ; 8(42): 73187-73197, 2017 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-29069862

RESUMO

Salt intake is highly associated with cardiac structure in patients with primary aldosteronism (PA). We investigated the association among dietary salt intake, aldosterone and left ventricular mass in patients with PA. We enrolled 158 patients with PA and 158 patients with essential hypertension. We measured 24-hour urinary sodium (UNa) and aldosterone (UAldo) level and echocardiography parameters. In patients with PA, the UAldo level was positively correlated with left ventricular mass index (LVMI; r=0.231, p=0.007). The UNa level was not linearly correlated with left ventricular structural parameters in patients with PA. To test if UNa has a non-linear relationship with LVMI among patients with PA, we categorized the participants according to the tertile of UNa (low, median, and high tertile). PA patients with medium tertile of UNa had significant lower LVMI than the other two groups (LVMI: 144.1 ± 42.9, 121.1 ± 33.4, and 136.7 ± 32.8 g/m2, from the lowest to the highest tertile of Una; analysis of variance p=0.006, post-hoc p <0.05). Multifactor analysis of variance confirmed this finding after adjustment for clinical parameters. Post-hoc analyses revealed that the high UNa tertile was associated with higher left ventricular end-diastolic volume compared with medium UNa tertile; while the low UNa tertile was associated with higher mean wall thickness compared with medium UNa tertile. The findings imply the reasons for increased LVMI may be different in patients with the highest and lowest UNa tertile. In conclusion, the medium tertile of 24-hour UNa is associated with lowest LVMI in patients with PA.

9.
Oncotarget ; 8(2): 2381-2390, 2017 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-27924061

RESUMO

Myocardial fibrosis leads to a restrictive diastolic filling pattern of the left ventricle which is associated with a poor prognosis in patients with heart failure. We investigated the relationship between cardiac fibrosis and restrictive filling pattern of the left ventricle measured by Tc99m left ventriculography in patients with chronic symptomatic heart failure. Serum cardiac extracellular matrix markers including type I and III aminoterminal propeptide of procollagen (PINP and PIIINP), matrix metalloproteinase-2,9 (MMP-2,9), and tissue inhibitor of MMP-1 (TIMP-1) were analyzed. Fifty-one (39 males) patients were enrolled. Their median age was 51.8 years, and median left ventricular ejection fraction was 31.9%. Time to peak filling rate of the left ventricle was significantly correlated with serum levels of the three cardiac extracellular matrix markers (TIMP-1, PIIINP, and MMP-2). The patients with a restrictive diastolic filling pattern of the left ventricle (time to peak filling rate ≤ 154 ms) had significantly higher levels of these extracellular matrix markers. In receiver operating characteristic curve analysis, areas under the curve of PIIINP, TIMP-1, and MMP-2 were 0.758, 0.695, and 0.751 to predict the presence of a restrictive pattern. In C-statistics, all three cardiac extracellular matrix markers significantly increased the area under the curve after adding creatinine. In net reclassification improvement and integrated discrimination improvement models, PIIINP and MMP-2 significantly improved the predictive power of age, creatinine and brain natriuretic peptide. In conclusion, serum extracellular matrix markers are significantly correlated with restrictive diastolic filling pattern of the left ventricle in patients with heart failure.


Assuntos
Biomarcadores/sangue , Fibrose Endomiocárdica/sangue , Insuficiência Cardíaca/diagnóstico , Ventriculografia com Radionuclídeos/métodos , Volume Sistólico/fisiologia , Tecnécio , Disfunção Ventricular Esquerda/diagnóstico , Adulto , Idoso , Fibrose Endomiocárdica/complicações , Fibrose Endomiocárdica/fisiopatologia , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Sensibilidade e Especificidade , Tecnécio/química , Disfunção Ventricular Esquerda/sangue , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/fisiopatologia
10.
J Investig Med ; 64(6): 1109-13, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27190071

RESUMO

UNLABELLED: Primary aldosteronism has been associated with myocardial fibrosis, and is the most common cause of secondary hypertension. We previously showed that aldosterone can induce the secretion of galectin-3. The aim of this study was to investigate the association between myocardial fibrosis and plasma galectin-3 level in patients with primary aldosteronism. We prospectively analyzed 11 patients with aldosterone-producing adenoma (APA) who received adrenalectomy from December 2006 to October 2008, and 17 patients with essential hypertension as controls. Levels of plasma galectin-3 were determined in both groups, and both groups underwent echocardiography with cyclic variations of integrated backscatter (CVIBS) to characterize tissue initially and 1 year after surgery in the APA group. Diastolic blood pressure, concentration of plasma aldosterone and aldosterone-renin ratio were significantly higher, and serum potassium level and plasma renin activity significantly lower in the APA group compared to the controls. In addition, left ventricular mass index was significantly higher and CVIBS significantly lower in the APA group (7.3±2.0 vs 9.2±1.7 dB, p=0.015). Furthermore, the concentration of plasma galectin-3 was significantly higher in the APA group (2.1±0.9 vs 1.1±0.6 ng/mL, p=0.005) compared to the controls. CVIBS was correlated to plasma galectin-3 level. In the APA group, CVIBS increased significantly (7.3±2.0 to 9.2±2.4 dB, p=0.032) and plasma galectin-3 decreased (2.1±0.9 to 1.2±0.6, p=0.049) 1 year postadrenalectomy. The patients with APA had increased myocardial fibrosis, and this was associated with a higher plasma galectin-3 level. Both increased myocardial fibrosis and plasma galectin-3 level recovered at least partially after adrenalectomy. TRIAL REGISTRATION NUMBER: 200611031R; Results.


Assuntos
Aldosterona/metabolismo , Galectina 3/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Adrenalectomia , Eletrocardiografia , Feminino , Fibrose , Seguimentos , Galectina 3/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos
11.
Hypertension ; 67(6): 1309-20, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27113051

RESUMO

Aldosterone induces myocardial fibrosis. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a key factor of myocardial fibrosis. This study tested the hypothesis that aldosterone induces TIMP-1 expression and contributes to the fibrotic process. We prospectively enrolled 54 patients with primary aldosteronism, and measured plasma TIMP-1 and echocardiographic parameters. In the cell study, we investigated the possible molecular mechanism by which aldosterone induces TIMP-1 secretion and the effects on collagen accumulation. In the animal study, we measured serum TIMP-1 levels, cardiac TIMP-1 levels, and cardiac structure in an aldosterone infusion mouse model using implantation of aldosterone pellets. In patients with primary aldosteronism, plasma TIMP-1 was correlated with 24-hour urinary aldosterone, left ventricular mass, and impairment of left ventricular diastolic function. In human cardiac fibroblasts, TIMP-1 protein and mRNA expressions were significantly increased by aldosterone through the glucocorticoid receptor/PI3K/Akt/nuclear factor-κB pathway. TIMP-1 small-interfering RNA significantly reduced aldosterone-induced collagen accumulation, and aldosterone did not alter the levels of collagen1a1 or matrix metalloproteinase-1 mRNA. The aldosterone-induced TIMP-1 expression was inversely related to matrix metalloproteinase-1 activity. Furthermore, in the animal model, the serum and cardiac levels of TIMP-1 were significantly elevated in the mice that received aldosterone infusion. This elevation was blocked by RU-486 but not by eplerenone, suggesting that the effect was through glucocorticoid receptors. In a long-term aldosterone infusion model, serum TIMP-1 was associated with serum aldosterone level, cardiac structure, and fibrosis. In conclusion, aldosterone induced TIMP-1 expression in vivo and in vitro. This increased TIMP-1 expression resulted in enhanced collagen accumulation via the suppression of matrix metalloproteinase-1 activity.


Assuntos
Colágeno/metabolismo , Hiperaldosteronismo/fisiopatologia , Metaloproteinase 1 da Matriz/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Aldosterona/metabolismo , Análise de Variância , Animais , Biópsia por Agulha , Western Blotting , Modelos Animais de Doenças , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibrose/genética , Fibrose/patologia , Regulação da Expressão Gênica , Humanos , Hiperaldosteronismo/metabolismo , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/patologia , RNA Mensageiro/genética , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real/métodos , Transdução de Sinais
12.
J Clin Endocrinol Metab ; 100(11): 4339-47, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26401591

RESUMO

CONTEXT: The effect of aldosterone on vascular smooth muscle cell function is still unclear. One method to measure vascular smooth muscle cell function is endothelial-independent vascular dilation, for which the key factor is sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA). OBJECTIVE: Our objective was to investigate the effect of aldosterone on vascular smooth muscle cell function and SERCA regulation. DESIGN: We prospectively analyzed 35 patients with primary aldosteronism (PA; 32 patients with aldosterone-producing adenoma and three patients with idiopathic hyperaldosteronism) and 30 patients with essential hypertension (EH) who were enrolled as the control group. Flow and nitrate-mediated dilation were performed in both groups and 1 year after adrenalectomy in the patients with aldosterone-producing adenoma. In addition, we investigated the effect of aldosterone on SERCA regulation in human aortic smooth muscle cells. SETTING: This study took place in an academic clinical research center. PARTICIPANTS: Participants included 35 patients with PA and 30 patients with EH. INTERVENTIONS: Adrenalectomy was undertaken in patients with aldosterone-producing adenoma. RESULTS: The PA patients had significantly lower flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) values than the patients with EH (FMD: 13 ± 6 vs 16 ± 4; NMD: 16 ± 6 vs 19 ± 5; both P < .05). FMD/NMD were significantly correlated with log 24 hour-urine aldosterone (FMD: r = -0.287, P = .048; NMD: r = -0.402, P = .005) but not blood pressure. The impaired FMD and NMD values were significantly restored 1 year after adrenalectomy (FMD: 11 ± 4 to 19 ± 7; NMD: 15 ± 6 to 21 ± 6; both P < .01). Under confocal microscopy, aldosterone was shown to suppress the expression of SERCA2a of human aortic smooth muscle cells. Aldosterone significantly suppressed the expression of SERCA2a from 10(-8) M in mRNA and protein levels. This suppression was through down-regulation of mineralocorticoid receptor dependent mitochondrial transcription factors A and B2. CONCLUSIONS: Aldosterone impairs vascular smooth muscle cell function and suppresses SERCA 2a expression.


Assuntos
Aldosterona/farmacologia , Hiperaldosteronismo/fisiopatologia , Músculo Liso Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Adrenalectomia , Adulto , Pressão Sanguínea , Células Cultivadas , Feminino , Humanos , Hiperaldosteronismo/metabolismo , Hiperaldosteronismo/cirurgia , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/citologia , Nitratos/farmacologia , Estudos Prospectivos , Interferência de RNA , RNA Mensageiro/biossíntese , Receptores de Mineralocorticoides/efeitos dos fármacos , Receptores de Mineralocorticoides/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Resultado do Tratamento
13.
Sci Rep ; 5: 11249, 2015 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-26282603

RESUMO

Excess aldosterone secretion in patients with primary aldosteronism (PA) impairs their cardiovascular system. Heart rhythm complexity analysis, derived from heart rate variability (HRV), is a powerful tool to quantify the complex regulatory dynamics of human physiology. We prospectively analyzed 20 patients with aldosterone producing adenoma (APA) that underwent adrenalectomy and 25 patients with essential hypertension (EH). The heart rate data were analyzed by conventional HRV and heart rhythm complexity analysis including detrended fluctuation analysis (DFA) and multiscale entropy (MSE). We found APA patients had significantly decreased DFAα2 on DFA analysis and decreased area 1-5, area 6-15, and area 6-20 on MSE analysis (all p < 0.05). Area 1-5, area 6-15, area 6-20 in the MSE study correlated significantly with log-transformed renin activity and log-transformed aldosterone-renin ratio (all p < = 0.01). The conventional HRV parameters were comparable between PA and EH patients. After adrenalectomy, all the altered DFA and MSE parameters improved significantly (all p < 0.05). The conventional HRV parameters did not change. Our result suggested that heart rhythm complexity is impaired in APA patients and this is at least partially reversed by adrenalectomy.


Assuntos
Aldosterona/metabolismo , Arritmias Cardíacas/fisiopatologia , Frequência Cardíaca , Hiperaldosteronismo/fisiopatologia , Modelos Cardiovasculares , Arritmias Cardíacas/etiologia , Relógios Biológicos , Simulação por Computador , Eletrocardiografia Ambulatorial/métodos , Feminino , Humanos , Hiperaldosteronismo/complicações , Masculino , Pessoa de Meia-Idade
14.
J Hypertens ; 33(9): 1922-30; discussion 1930, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26103125

RESUMO

OBJECTIVE: To test if collagen markers are associated with aldosterone-induced diastolic dysfunction. BACKGROUND: Although primary aldosteronism is associated with more prominent cardiac remodeling and diastolic dysfunction, the reversibility of diastolic function is unclear. In addition, there is no known biomarker associated with aldosterone-induced diastolic dysfunction. METHODS: We enrolled 27 patients with aldosterone-producing adenoma (APA) preparing for adrenalectomy, and 27 patients with essential hypertension prospectively from October 2006 to March 2010 at a tertiary referral center. Plasma matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were measured, and echocardiography including tissue Doppler images was performed in both groups and 1 year after receiving adrenalectomy in the APA group. RESULTS: The baseline plasma TIMP-1 level (88.4 ±â€Š38.7 vs. 63.6 ±â€Š32.5 ng/ml; P = 0.014), left ventricular mass index (LVMI), and E/E' ratio (11.5 ±â€Š2.9 vs. 9.0 ±â€Š2.1; P < 0.001) were significantly higher in the APA group. The baseline plasma TIMP-1 level significantly correlated with the E/E' ratio, LVMI, interventricular septum, and left atrial diameter. The plasma MMP-2 level did not correlate with the left ventricular structure parameters, except for interventricular septum thickness. After adrenalectomy, LVMI and E/E' ratio improved significantly. The postadrenalectomy plasma TIMP-1 levels, but not MMP-2 levels, also decreased. The change of plasma TIMP-1 levels was negatively associated with the postadrenalectomy E/E' ratio after adjustment for age, sex, BMI, and mean blood pressure (ß-coefficient = - 3.6, P = 0.004). CONCLUSION: Excess of aldosterone induces cardiac diastolic dysfunction, which is reversible by adrenalectomy. TIMP-1 is associated with the aldosterone-induced diastolic dysfunction.


Assuntos
Neoplasias do Córtex Suprarrenal/sangue , Adenoma Adrenocortical/sangue , Ventrículos do Coração/diagnóstico por imagem , Hiperaldosteronismo/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Neoplasias do Córtex Suprarrenal/complicações , Neoplasias do Córtex Suprarrenal/cirurgia , Adrenalectomia , Adenoma Adrenocortical/complicações , Adenoma Adrenocortical/cirurgia , Adulto , Aldosterona/sangue , Diástole , Ecocardiografia Doppler , Hipertensão Essencial , Feminino , Humanos , Hiperaldosteronismo/etiologia , Hiperaldosteronismo/cirurgia , Hipertensão/sangue , Hipertensão/diagnóstico por imagem , Hipertensão/patologia , Masculino , Metaloproteinase 2 da Matriz/sangue , Pessoa de Meia-Idade , Resultado do Tratamento
15.
Int J Med Sci ; 12(5): 369-77, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26005371

RESUMO

BACKGROUND: Glomerular hyperfiltration has been recently noticed as an important issue in primary aldosteronism (PA) patients. However, its effect on the cardiovascular system remains unknown. METHODS: We prospectively analyzed 47 PA patients including 11 PA patients with estimated glomerular filtration rate (eGFR) > 130 ml/min per 1.73 m2 (group 1), and 36 PA patients with eGFR 90-110 ml/min per 1.73 m2 (group 2). Fourteen essential hypertension (EH) patients with eGFR 90-110 ml/min per 1.73 m2 were included as the control group (group 3). Echocardiography including left ventricular mass index (LVMI) measurement and tissue Doppler imaging (TDI) was performed. Predicted left ventricular mass (LVM) was calculated. Inappropriate LVM was defined as an excess of > 35% from the predicted value. RESULTS: The value of LVMI decreased significantly in order from groups 1 to 3 (group 1>2>3). While group 2 had a significantly higher percentage of inappropriate LVM than group 3, the percentage of inappropriate LVM were comparable in groups 1 and 2. Group 1 had a higher mitral E velocity, E/A ratio than that of group 2. In the TDI study, the E/E' ratio also decreased significantly in order from groups 1 to 3 (group 1>2>3). Group 2 had lower E' than that of group 3, although the E' of group 1 and 2 were comparable. CONCLUSIONS: Although PA patients with glomerular hyperfiltration were associated with higher LVMI, higher mitral E velocity, higher E/E' ratio, they had comparable E' with PA patients with normal GFR. This phenomenon may be explained by higher intravascular volume in this patient group.


Assuntos
Taxa de Filtração Glomerular , Ventrículos do Coração/fisiopatologia , Hiperaldosteronismo/fisiopatologia , Adulto , Ecocardiografia , Hipertensão Essencial , Feminino , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Regressão , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia
16.
J Renin Angiotensin Aldosterone Syst ; 16(2): 353-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25143326

RESUMO

INTRODUCTION: Hypokalemia in primary aldosteronism (PA) patients correlates with higher levels of cardiovascular events and altered left ventricular geometry. However, the influence of aldosterone on microvascular endothelial function and the effect of hypokalemia on the vascular structure still remain unclear. OBJECTIVES: We investigated the peripheral arterial functions, including the endothelial function of microvasculature and arterial stiffness in PA and essential hypertension (EH) patients, and the correlation between hypokalemia and peripheral arterial function among PA patients. METHODS: Twenty patients diagnosed as EH and 37 patients with PA were enrolled in this study. Reactive hyperemia index (RHI) and the augmentation index (AI) were obtained by non-invasive peripheral arterial tonometry. RESULTS: Twenty EH patients and a total of 37 PA patients, including 21 patients with normokalemia and 16 patients with hypokalemia, were enrolled and divided into groups 1, 2 and 3 respectively. PA patients had significantly higher AI (p=0.024) but not RHI than EH patients. RHI showed no difference between groups 1, 2 and 3. Group 3 had higher AI than either group 1 or group 2. In the whole study population, serum potassium level, after multivariate regression analysis testing, was the only factor associated with AI (ß= -0.102; p=0.002). In PA patients, serum potassium level was the only significant factor correlated with AI. (r= -0.458; p=0.004) CONCLUSIONS: PA patients had higher arterial stiffness but comparable microvascular endothelial function to EH patients. Hypokalemia correlated with arterial stiffness but not microvascular endothelial function in PA patients.


Assuntos
Endotélio Vascular/fisiopatologia , Hiperaldosteronismo/complicações , Hiperaldosteronismo/fisiopatologia , Hipopotassemia/complicações , Hipopotassemia/fisiopatologia , Microvasos/fisiopatologia , Rigidez Vascular/fisiologia , Adulto , Feminino , Humanos , Masculino , Manometria , Pessoa de Meia-Idade , Análise Multivariada , Análise de Regressão
17.
PLoS One ; 9(9): e95254, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25180794

RESUMO

CONTEXT: Patients with primary aldosteronism are associated with increased myocardial fibrosis. Galectin-3 is one of the most important mediators between macrophage activation and myocardial fibrosis. OBJECTIVE: To investigate whether aldosterone induces galectin-3 secretion in vitro and in vivo. METHODS AND RESULTS: We investigated the possible molecular mechanism of aldosterone-induced galectin-3 secretion in macrophage cell lines (THP-1 and RAW 264.7 cells). Aldosterone induced galectin-3 secretion through mineralocorticoid receptors via the PI3K/Akt and NF-κB transcription signaling pathways. In addition, aldosterone-induced galectin-3 expression enhanced fibrosis-related factor expression in fibroblasts. We observed that galectin-3 mRNA from peripheral blood mononuclear cells and serum galectin-3 levels were both significantly increased in mice implanted with aldosterone pellets on days 7 and 14. We then conducted a prospective preliminary clinical study to investigate the association between aldosterone and galectin-3. Patients with aldosterone-producing adenoma had a significantly higher plasma galectin-3 level than patients with essential hypertension. One year after adrenalectomy, the plasma galectin-3 level had decreased significantly in the patients with aldosterone-producing adenoma. CONCLUSION: This study demonstrated that aldosterone could induce galectin-3 secretion in vitro and in vivo.


Assuntos
Aldosterona/farmacologia , Galectina 3/metabolismo , Adrenalectomia , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose , Galectina 3/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperaldosteronismo/genética , Hiperaldosteronismo/metabolismo , Hiperaldosteronismo/patologia , Hiperaldosteronismo/cirurgia , Masculino , Camundongos , Miocárdio/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
18.
Int J Med Sci ; 11(11): 1098-106, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25170292

RESUMO

BACKGROUND: Galectin-3 (Gal-3) shows the ability of survival prediction in heart failure (HF) patients. However, Gal-3 is strongly associated with serum markers of cardiac extracellular matrix (ECM) turnover. The aim of this study is to compare the impact of Gal-3 and serum markers of cardiac ECM turnover on prognostic prediction of chronic systolic HF patients. METHODS: Serum Gal-3, brain natriuretic peptide (BNP), extracellular matrix including type I and III aminoterminal propeptide of procollagen (PINP and PIIINP), matrix metalloproteinase-2, 9 (MMP-2, 9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were analyzed. Cox regression analysis was used for survival analysis. RESULTS: A total of 105 (81 male) patients were enrolled. During 980±346 days follow-up, 17 patients died and 36 episodes of HF admission happened. Mortality of these patients was significantly associated with the log PIIINP (ß= 15.380; P=0.042), log TIMP-1(ß= 44.530; P=0.003), log MMP-2 (ß= 554.336; P<0.001), log BNP (ß= 28.273; P=0.034). Log Gal-3 (ß= 7.484; P=0.066) is borderline associated with mortality. Mortality or first HF admission of these patients was significantly associated with the log TIMP-1(ß= 16.496; P=0.006), log MMP-2 (ß= 221.864; P<0.001), log BNP (ß= 5.999; P=0.034). Log Gal-3 (ß= 4.486; P=0.095) only showed borderline significance. In several models adjusting clinical parameters, log MMP-2 was significantly associated with clinical outcome. In contrast, log Gal-3 was not. CONCLUSION: The prognostic strength of MMP-2 to clinical outcome prediction in HF patients is stronger than Gal-3.


Assuntos
Galectina 3/sangue , Insuficiência Cardíaca Sistólica/sangue , Insuficiência Cardíaca Sistólica/patologia , Idoso , Feminino , Humanos , Masculino , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Valor Preditivo dos Testes , Pró-Colágeno/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue
19.
Clin Biochem ; 47(13-14): 1329-32, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24892901

RESUMO

OBJECTIVE: To investigate the association between aldosterone and cardiac diastolic dysfunction. DESIGN AND METHODS: We prospectively enrolled 20 patients with primary aldosteronism (PA) and 22 patients with essential hypertension (EH). Plasma aldosterone concentration, plasma renin activity, and 24-h urine aldosterone level were measured. Echocardiography, including tissue Doppler image recordings, was performed. RESULTS: PA patients had a significantly higher left ventricular (LV) mass index and worse LV diastolic function than those in EH patients. Among various measures of aldosterone, log-transformed 24-h urine aldosterone level had the most consistent correlation with diastolic function. CONCLUSIONS: Aldosterone is strongly associated with LV diastolic dysfunction. Twenty-four hour urine aldosterone is a good indicator to evaluate the impact of aldosterone on LV diastolic function.


Assuntos
Aldosterona/urina , Hiperaldosteronismo/fisiopatologia , Hiperaldosteronismo/urina , Hipertensão/fisiopatologia , Hipertensão/urina , Função Ventricular Esquerda/fisiologia , Adulto , Aldosterona/sangue , Ecocardiografia/métodos , Hipertensão Essencial , Feminino , Humanos , Hiperaldosteronismo/sangue , Hipertensão/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Disfunção Ventricular Esquerda/sangue , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/urina
20.
Clin Biochem ; 2013 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-23376327

RESUMO

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

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