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2.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(9): 1128-1132, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31657338

RESUMO

OBJECTIVE: To investigate the effect of circadian heart rate variation on short-term and long-term mortality in intensive care unit (ICU) patients. METHODS: A retrospective cohort study was conducted. A total of 32 536 ICU patients were recorded from 2001 to 2008 published by Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC-II v2.6) in April 2011. The circadian heart rate variation was defined as the ratio of mean nighttime (23:00 to 07:00) heart rate to mean daytime (07:00 to 23:00) heart rate. The 28-day mortality and 1-year mortality were defined as outcome events. The information such as age, gender, ethnicity, first sequential organ failure assessment (SOFA) score, first simplified acute physiology score I (SAPS I), usage of sedatives and catecholamines within 24 hours admission of ICU, clinical complications [hypertension, chronic obstructive pulmonary disease (COPD), diabetes with or without complications, congestive heart failure, liver disease, renal failure, etc.], and the complete heart rate records within 24 hours after ICU admission were collected. Cox proportional risk regression models were used to investigate the association between circadian heart rate variation and 28-day mortality and 1-year mortality in ICU patients. Besides, subgroup analysis was also performed in patients with different first SOFA scores. RESULTS: Totally 15 382 ICU patients in MIMIC-II database were enrolled, excluding the patients without heart rate records or death records, using pacemaker with arrhythmia, without SOFA or SAPS I score records. Finally, 9 439 patients were enrolled in the study cohort. (1) Cox regression analysis of the whole patient showed that the higher circadian heart rate variation was correlated with the increased 28-day mortality [hazard ratio (HR) = 1.613, 95% confidence interval (95%CI) was 1.338-1.943, P < 0.001] and 1-year mortality (HR = 1.573, 95%CI was 1.296-1.908, P < 0.001). After adjustment for demographic factors (age, gender and ethnicity), severity of illness (SOFA and SAPS I scores), clinical complications (hypertension, COPD, diabetes with or without complications, congestive heart failure, liver disease, renal failure, etc.), and influence of medications (sedatives and catecholamines), the night-day heart rate ratio was also correlated with 28-day mortality (HR = 1.256, 95%CI was 1.018-1.549, P = 0.033) and 1-year mortality (HR = 1.249, 95%CI was 1.010-1.545, P = 0.040). (2) According to the SOFA score (median value of 5), the patients were divided into two subgroups, in which 5 478 patients with SOFA score ≤ 5 and 3 961 patients with SOFA score > 5. Cox regression subgroup analysis showed that circadian heart rate variation was related with higher 28-day mortality (HR = 1.430, 95%CI was 1.164-1.756, P = 0.001) and 1-year mortality (HR = 1.393, 95%CI was 1.123-1.729, P = 0.003) in patients with SOFA score > 5. After adjustment for covariates, the 28-day mortality (HR = 1.279, 95%CI was 1.032-1.584, P = 0.025) and 1-year mortality (HR = 1.255, 95%CI was 1.010-1.558, P = 0.040) also increased with the increasing of night-day heart rate ratio in patients with SOFA score > 5. However, the relationships did not exist in patients with SOFA score ≤ 5. CONCLUSIONS: In ICU patients, the 28-day mortality and 1-year mortality increase with the higher circadian heart rate variation, which indicates that the circadian heart rate variation in ICU patients is positively correlated with the short-term and long-term mortality, especially in patients with relatively severe illness.


Assuntos
Relógios Circadianos , Frequência Cardíaca/fisiologia , Unidades de Terapia Intensiva , Mortalidade/tendências , Cuidados Críticos , Humanos , Escores de Disfunção Orgânica , Prognóstico , Estudos Retrospectivos
3.
Med Sci Monit ; 25: 5401-5407, 2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31326975

RESUMO

BACKGROUND The aim of this study was to assess the clinical efficacy and safety of mechanical ventilation combined with fiberoptic bronchoalveolar lavage in patients with severe pulmonary infection. MATERIAL AND METHODS We randomly divided 81 patients with severe pulmonary infection into a control group (n=40) and an observation group (n=41). Both groups were treated using mechanical ventilation, and observation group additionally received assistive fiberoptic bronchoalveolar lavage. RESULTS The cure rate and effectiveness rate in the observation group were higher than in the control group (P<0.05, χ²=3.2), and the incidence of ventilator-associated pneumonia in the observation group was significantly lower than that in the control group (P<0.05, χ²=9.4). The partial pressure of oxygen (PaO2) and oxygen saturation (SaO2) were higher in the observation group than in the control group (P<0.05, t=3.862, t=33.595), whereas the partial pressure of carbon dioxide (PaCO2) and respiratory rate were lower in the observation group than in the control group (P<0.05, t=3.307, t=5.043). The levels of C-reactive protein (CRP), tumor necrosis factor-a (TNF-alpha), interleukin-6 (IL-6), and interleukin-8 (IL-8) in the 2 groups were lower after treatment than before treatment (all P<0.05), and the levels in the observation group were lower than those in the control group (all P<0.05). Hospital stay, infection control window appearance time, invasive mechanical ventilation time, and total mechanical ventilation time in the observation group were shorter than those in the control group (P<0.05, t=13.990, t=8.643, t=9.717, t=8.980). CONCLUSIONS Mechanical ventilation combined with fiberoptic bronchoalveolar lavage can effectively improve the curative effects and the blood gas and inflammation indicators in patients.

4.
BMC Cardiovasc Disord ; 19(1): 35, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30717670

RESUMO

BACKGROUND: Previous studies have found a connection between left coronary artery dominance and worse prognoses in patient with acute coronary syndrome, which remains a predominant cause of morbidity and mortality globally. The aim of this study was to investigate whether coronary dominance is associated with the incidence of acute inferior myocardial infarction (MI). METHODS: Between January 2011 and November 2014, 265 patients with acute inferior MI and 530 age-matched and sex-matched controls were recruited for a case-control study in the Second Affiliated Hospital of Xi'an Jiaotong University in Xi'an, China. All participants underwent coronary angiography. The exclusion criteria included history of coronary artery bypass graft surgery, chronic or systemic diseases (including hepatic failure, kidney failure, hypothyroidism and Grave's disease), ventricular fibrillation, and known allergy to iodinated contrast agent. Patients with left- or co-dominant anatomies were placed into the LD group and those with right-dominant anatomy were included in the RD group. The association of acute inferior MI and coronary dominant anatomy were assessed using multivariable conditional logistic regression, and to estimate the odds ratio (OR) and 95% confidence interval (95%CI). RESULTS: Distributions of right dominance were significantly different between the acute inferior MI group and control group (94.0% vs. 87.9%, P = 0.018). Univariable conditional logistic regression revealed that right dominance may be a risk factor for the incident acute inferior MI (OR: 2.137; 95% CI: 1.210-3.776; P = 0.009). After adjusting for baseline systolic blood pressure, heart rate, smoking status, diabetes mellitus, hypertension, hyperlipidaemia, and family history of coronary artery disease, results of multivariate conditional logistic regression showed that right dominance was associated with the incidence of acute inferior MI (OR: 2.396; 95% CI: 1.328-4.321; P = 0.004). CONCLUSIONS: Right coronary dominance may play a disadvantageous role in the incidence of acute inferior MI. However, further studies are needed to verify our findings, especially with regard to the underlying mechanisms.


Assuntos
Angiografia por Tomografia Computadorizada , Angiografia Coronária/métodos , Estenose Coronária/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Infarto Miocárdico de Parede Inferior/diagnóstico por imagem , Infarto do Miocárdio sem Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Idoso , China/epidemiologia , Circulação Coronária , Estenose Coronária/epidemiologia , Estenose Coronária/fisiopatologia , Vasos Coronários/fisiopatologia , Feminino , Humanos , Incidência , Infarto Miocárdico de Parede Inferior/epidemiologia , Infarto Miocárdico de Parede Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio sem Supradesnível do Segmento ST/epidemiologia , Infarto do Miocárdio sem Supradesnível do Segmento ST/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/epidemiologia , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Índice de Gravidade de Doença
5.
Oncotarget ; 8(40): 67218-67226, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28978028

RESUMO

Here, we found that hernandezine, a novel AMPK activator, inhibited LPS-induced TNFα expression/production in human macrophage cells (THP-1 and U937 lines). Activation of AMPK is required for hernandezine-induced anti-LPS response. AMPKα shRNA or dominant negative mutation (T172A) blocked hernandezine-induced AMPK activation, which almost completely reversed anti-LPS activity by hernandezine. Exogenous expression of the constitutively activate AMPKα (T172D, caAMPKα) also suppressed TNFα production by LPS. Remarkably, hernandezine was unable to further inhibit LPS-mediated TNFα production in caAMPKα-expressing cells. Hernandezine inhibited LPS-induced reactive oxygen species (ROS) production and nuclear factor kappa B (NFκB) activation. Treatment of hernandezine in ex-vivo cultured primary human peripheral blood mononuclear cells (PBMCs) also largely attenuated LPS-induced TNFα production. Together, we conclude that AMPK activation by hernandezine inhibits LPS-induced TNFα production in macrophages/monocytes.

6.
Exp Lung Res ; 41(8): 435-43, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26317171

RESUMO

It has been shown that activation of Notch3 signaling is involved in the development of pulmonary arterial hypertension (PAH) by stimulating pulmonary arteries remodeling, while the molecular mechanisms underlying this are still largely unknown. The aims of this study are to address these issues. Monocrotaline dramatically increased right ventricle systolic pressure to 39.0 ± 2.6 mmHg and right ventricle hypertrophy index to 53.4 ± 5.3% (P < 0.05 versus control) in rats, these were accompanied with significantly increased proliferation and reduced apoptosis of pulmonary vascular cells as well as pulmonary arteries remodeling. Treatment of PAH model with specific Notch inhibitor DAPT significantly reduced right ventricle systolic pressure to 26.6 ± 1.3 mmHg and right ventricle hypertrophy index to 33.5 ± 2.6% (P < 0.05 versus PAH), suppressed proliferation and enhanced apoptosis of pulmonary vascular cells as well as inhibited pulmonary arteries remodeling. Our results further indicated that level of Notch3 protein and NICD3 were increased in MCT-induced model of PAH, this was accompanied with elevation of Skp2 and Hes1 protein level and reduction of P27Kip1. Administration of rats with DAPT-prevented MCT induced these changes. Our results suggest that Notch3 signaling activation stimulated pulmonary vascular cells proliferation by Skp2-and Hes1-mediated P27Kip1 reduction, and Notch3 might be a new target to treat PAH.


Assuntos
Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/metabolismo , Monocrotalina/farmacologia , Artéria Pulmonar/metabolismo , Receptores Notch/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Hipertrofia Ventricular Direita/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Artéria Pulmonar/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor Notch3 , Transdução de Sinais/efeitos dos fármacos
7.
Int J Mol Med ; 36(1): 316-22, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26017061

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disorder with high morbidity and mortality, and is characterized by excessive growth of endothelial cells. Recently, the mammalian target of rapamycin (mTOR) has attracted increasing attention due to its potential as a therapeutic target against certain diseases associated with proliferative and metabolic abnormalities. However, the effect on mTOR on PAH has not yet been elucidated. In the present study, a marked downregulation of mTOR was observed in PAH patients. Following construction of a mouse model of PAH by chronic exposure to hypoxia, adenovirus-mediated upregulation of mTOR significantly attenuated right ventricular systolic pressure, right ventricular hypertrophy and wall thickness of pulmonary arterioles, indicating a protective effect of mTOR on PAH. Further analysis confirmed that mTOR overexpression inhibited autophagy triggered by hypoxia through blocking light chain 3 II expression and increasing p62 levels. In vitro, hypoxia enhanced the proliferation of human pulmonary artery endothelial cells (PAECs), which was markedly abrogated by mTOR overexpression. Of note, upregulation of mTOR inhibited the hypoxia-induced autophagy pathway, which contributed to cell proliferation, while silencing of autophagy by RNA interference with ATG5 significantly inhibited cell proliferation. In conclusion, the results of the present study suggested a potential protective effect of mTOR on the progression of PAH by suppressing PAEC proliferation through blocking the autophagic pathway. Therefore, the present study suggested that mTOR is a promising therapeutic agent against PAH.


Assuntos
Autofagia/fisiologia , Hipóxia Celular/fisiologia , Hipertensão Pulmonar/patologia , Proteínas Associadas aos Microtúbulos/genética , Serina-Treonina Quinases TOR/biossíntese , Adulto , Animais , Proteína 5 Relacionada à Autofagia , Linhagem Celular , Proliferação de Células , Regulação para Baixo , Células Endoteliais , Feminino , Humanos , Hipertrofia Ventricular Direita , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/biossíntese , Pessoa de Meia-Idade , Artéria Pulmonar/citologia , Interferência de RNA , RNA Interferente Pequeno , Proteínas de Ligação a RNA/biossíntese , Função Ventricular Direita
8.
DNA Cell Biol ; 33(4): 198-204, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24512183

RESUMO

Recently, autophagy has drawn more attention in cardiovascular disease as it has important roles in lipid metabolism. Mammalian target of rapamycin (mTOR) is a key regulator of autophagy; however, its effect on atherosclerosis and the underlying mechanism remains undefined. In this study, an obvious upregulation of mTOR and p-mTOR protein was observed in macrophage-derived foam cells. Blocking mTOR expression with specific small interference RNA (siRNA) dramatically suppressed foam cell formation, accompanied by a decrease of lipid deposition. Further mechanistic analysis indicated that suppressing mTOR expression significantly upregulated autophagic marker LC3 expression and downregulated autophagy substrate p62 levels, indicating that mTOR silencing triggered autophagosome formation. Moreover, blocking mTOR expression obviously accelerated neutral lipid delivery to lysosome and cholesterol efflux from foam cells, implying that mTOR could induce macrophage foam cell formation by suppressing autophagic pathway. Further, mTOR silencing significantly upregulated ULK1 expression, which was accounted for mTOR-induced foam cell formation via autophagic pathway as treatment with ULK1 siRNA dampened LC3-II levels and increased p62 expression, concomitant with lipid accumulation and decreased cholesterol efflux from foam cells. Together, our data provide an insight into how mTOR accelerates the pathological process of atherosclerosis. Accordingly, blocking mTOR levels may be a promising therapeutic agent against atherosclerotic complications.


Assuntos
Autofagia/fisiologia , Células Espumosas/citologia , Regulação da Expressão Gênica/fisiologia , Metabolismo dos Lipídeos/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Compostos Azo , Células Espumosas/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipoproteínas LDL , Camundongos , Microscopia de Fluorescência , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , Serina-Treonina Quinases TOR/genética
9.
Nan Fang Yi Ke Da Xue Xue Bao ; 33(10): 1458-62, 2013 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-24144746

RESUMO

OBJECTIVE: To examine the correlation of the changes in the serum markers (C-reactive protein, endothelin-1, interleukin-6, and brain natriuretic peptide) with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension secondary to COPD. METHODS: A total of 174 COPD patients with acute exacerbation, admitted between February 2011 and February, 2013, were enrolled in this study, with 43 volunteers with normal pulmonary functions as controls. Pulmonary arterial pressure was determined by Doppler echocardiograph, and the severities (mild, moderate and severe) of PH secondary to COPD was evaluated. The levels of serum markers were determined using ELISA kits. RESULTS: The levels of serum markers in patients with COPD was significantly elevated compared with those of the control subjects (P<0.05), and further increased in patients with pulmonary hypertension secondary to COPD (P<0.05). A positive correlation was found between these serum markers and pulmonary artery pressure in COPD patients with mild and moderate pulmonary hypertension. In patients with severe pulmonary hypertension, only the serum level of brain natriuretic peptide continued to increase with pulmonary artery pressure (P<0.05), and the other markers did not further increase. CONCLUSIONS: Early and combined examination of these serum markers in patients with COPD can help to identify pulmonary hypertension in early stage and estimate the severity of pulmonary hypertension. Hemodynamic monitoring of the changes of these serum markers can be of important clinical value in the treatment of pulmonary hypertension secondary to COPD and in evaluation of the prognosis of COPD.


Assuntos
Biomarcadores/sangue , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/complicações , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/complicações , Idoso , Pressão Sanguínea , Proteína C-Reativa/metabolismo , Endotelina-1/sangue , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Interleucina-6/sangue , Masculino , Peptídeo Natriurético Encefálico/sangue , Doença Pulmonar Obstrutiva Crônica/fisiopatologia
10.
Int J Mol Med ; 32(5): 1215-21, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24043133

RESUMO

Atherosclerotic plaque destabilization and rupture leads to acute coronary syndromes which cause serious damage to human health worldwide. However, there is currently a lack of efficient therapeutic methods. Mammalian target of rapamycin (mTOR) has been suggested to be involved in the development of atherosclerotic plaques and serves as a therapeutic target. The present study was performed to determine whether RNA interference (RNAi) of mTOR in vivo by LV­mediated small hairpin RNA (shRNA) was capable of inhibiting the progression of atherosclerotic plaques. LV­mediated shRNA against mTOR (LV­shmTOR) was designed and obtained. Male apolipoprotein E­deficient mice were fed a high­fat diet and a constrictive collar was placed around the right carotid arteries of these mice to induce plaque formation. Eight weeks after surgery, mice were randomly divided into the mTOR RNA interference (LV­shmTOR) group, receiving treatment with LV­mTOR­shRNA; the LV­shCON group, receiving treatment with LV­non­specific­shRNA; and the control group, receiving treatment with phosphate­buffered saline. Following transfection, the mice were sacrificed to evaluate the effects of mTOR expression silencing on atherosclerosis. Transfection of LV­mTOR­shRNA markedly inhibited the mRNA and protein expression levels. Knockdown of mTOR ameliorated dysregulated blood lipid metabolism and stabilized aortic atherosclerotic plaques by decreasing the plaque area and increasing the fibrous cap and cap­to­core ratio. Furthermore, macrophages were decreased by silencing mTOR in atherosclerotic plaques. In addition, western blot analysis revealed that the knockdown of mTOR increased autophagy­related protein 13 (Atg13) dephosphorylation and light chain 3­I/light chain 3­II (LC3­I/LC3­II) ratios, both of which were associated with a high activity of autophagy, suggesting an increase of autophagy in atherosclerotic plaques. Moreover, genes including matrix metalloproteinase 2, monocyte chemoattractant protein 1 and tissue factor, which promote plaque instability, were downregulated by silencing mTOR. These results demonstrate that LV­mediated mTOR silencing by RNAi treatment induces macrophage autophagy and is a potential strategy for the treatment of atherosclerotic plaques.


Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/metabolismo , Aterosclerose/terapia , Autofagia/fisiologia , Lentivirus/genética , Interferência de RNA/fisiologia , Serina-Treonina Quinases TOR/genética , Animais , Apolipoproteínas E/genética , Aterosclerose/genética , Autofagia/genética , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Mutantes , Serina-Treonina Quinases TOR/metabolismo
11.
Nan Fang Yi Ke Da Xue Xue Bao ; 33(1): 26-9, 2013 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-23353150

RESUMO

OBJECTIVE: To examine whether calcineurin/NFAT signaling pathway mediates endothelin-1 (ET-1)-induced proliferation of pulmonary artery smooth muscle cells (PASMCs) by regulating phosphodiesterase-5 (PDE5) and the effect of the selective calcineurin inhibitor cyclosporine A and PDE5 inhibitor sildenafil on ET-1-induced PASMC proliferation. METHODS: PASMCs were treated with ET-1 to stimulate their proliferation with or without prior treatment of the cells with CsA or sildenafil. Calcineurin activity in the cells was measured using a calcineurin activity assay kit, PDE5 expression examined using immunoblotting, and cGMP level detected using a cGMP direct immunoassay kit. PASMC proliferation following the treatments was determined using [(3)H]thymidine incorporation assay. RESULTS: ET-1 caused a 2.05-fold increase in the cellular calcineurin activity, a 1.80-fold increase in PDE5 expression, and a 3.20-fold increase in the DNA synthesis rate, and reduced the cGMP level by 67%. Pretreatment of the cells with Cyclosporine blocked the effects of ET-1, and PDE5 inhibition by sildenafil pretreatment also abolished ET-1-induced reduction of cGMP level in the cells. Both Cyclosporine and sildenafil suppressed ET-1-stimulated PASMC proliferation. CONCLUSION: Activation of calcineurin/NFAT signaling pathway mediates ET-1-induced PASMC proliferation by stimulating PDE5 expression, which further degrades cGMP. Both Cyclosporine and sildenafil can suppress ET-1-stimulated PASMC proliferation in vitro.


Assuntos
Calcineurina/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Endotelina-1/farmacologia , Miócitos de Músculo Liso/citologia , Fatores de Transcrição NFATC/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , GMP Cíclico/metabolismo , Ciclosporina , DNA/biossíntese , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/enzimologia , Piperazinas , Artéria Pulmonar/citologia , Purinas , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Citrato de Sildenafila , Sulfonas
12.
Life Sci ; 89(17-18): 644-9, 2011 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-21851826

RESUMO

AIMS: To examine whether calcineurin/NFAT signaling pathway leads to proliferation of pulmonary artery smooth muscle cells (PASMCs) by regulating cell cycle proteins and whether the phosphodiesterase-5 (PDE5) inhibitor sildenafil affects calcineurin/NFAT-induced cell proliferation. MAIN METHODS: A [(3)H]thymidine incorporation assay was used to examine DNA synthesis (cell proliferation); cyclin A and NFATc2 expressions were determined by Western blot. Cyclin-dependent kinase 2 (CDK2) activity was measured with an in vitro kinase activity assay, and calcineurin and NFAT activity were evaluated using a calcineurin assay kit and a luciferase activity assay, respectively. A chemical inhibitor or siRNA transfection was used to inhibit calcineurin/NFAT signaling pathway. KEY FINDINGS: Serotonin dose-dependently stimulated cyclin A expression in PASMCs. This effect was accompanied by dose-dependent increases in CDK2 activity and the rate of DNA synthesis. At the same time, PASMCs treated with serotonin showed dose-dependent activation of calcineurin/NFAT signaling pathway. Inhibition of calcineurin activity by cyclosporine A or loss of NFATc2 protein by siRNA transfection abolished serotonin-induced cyclin A expression and consequent CDK2 activation and DNA synthesis. We further found that pretreatment of cells with sildenafil suppressed serotonin-triggered activation of calcineurin/NFATc2 signaling pathway and resultant cyclin A expression, CDK2 activation and cell proliferation, while the presence of DT-3 [a specific protein kinase G (PKG) peptide inhibitor] reversed the effects of sildenafil on PASMCs. SIGNIFICANCE: Our study suggests that enhanced PKG activity suppresses calcineurin/NFATc2 cascade-mediated cyclin A expression, CDK2 activation and PASMC proliferation to contribute to the overall effects of sildenafil in the treatment of pulmonary hypertension.


Assuntos
Calcineurina/metabolismo , Ciclina A/genética , Miócitos de Músculo Liso/efeitos dos fármacos , Fatores de Transcrição NFATC/metabolismo , Inibidores da Fosfodiesterase 5/farmacologia , Piperazinas/farmacologia , Artéria Pulmonar/citologia , Sulfonas/farmacologia , Animais , Calcineurina/genética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Fatores de Transcrição NFATC/genética , Artéria Pulmonar/efeitos dos fármacos , Purinas/farmacologia , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Citrato de Sildenafila
13.
FEBS Lett ; 579(1): 251-8, 2005 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-15620722

RESUMO

The abnormal hyperphosphorylation of tau protein is one of the hallmarks of Alzheimer disease and other tauopathies; as yet the exact role of various tau kinases in this pathology is not fully understood. Here, we show that injection of isoproterenol, an activator of cAMP-dependent kinase (PKA), into rat hippocampus bilaterally results in the activation of PKA, calcium/calmodulin-dependent kinase II and cyclin-dependent kinase-5, inhibition of protein phosphatase-2A, hyperphosphorylation of tau at several Alzheimer-like epitopes and a disturbance of spatial memory retention 48 h after the drug injection. These findings suggest the involvement of PKA and PKA-mediated signaling pathway in the Alzheimer-like tau hyperphosphorylation and memory impairment.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Hipocampo/enzimologia , Transtornos da Memória/enzimologia , Proteínas tau/metabolismo , Doença de Alzheimer/enzimologia , Animais , Proteínas Quinases Dependentes de Cálcio-Calmodulina/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Quinase 5 Dependente de Ciclina , Quinases Ciclina-Dependentes/metabolismo , Quinases Ciclina-Dependentes/fisiologia , Hipocampo/efeitos dos fármacos , Injeções , Isoproterenol/administração & dosagem , Transtornos da Memória/induzido quimicamente , Fosforilação/efeitos dos fármacos , Ratos , Comportamento Espacial/efeitos dos fármacos , Proteínas tau/análise
14.
Neurosci Lett ; 320(3): 156-60, 2002 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-11852185

RESUMO

Neurofilament (NF) subunits NF-H, NF-M and NF-L are hyperphosphorylated and elevated in Alzheimer disease (AD) brain. We investigated the level and phosphorylation states of NF subunits in lumbar cerebrospinal fluid (CSF) from living patients by bienzyme substrate-recycle enzyme-linked immunosorbent assay. We found: (i), that the levels of phosphorylated NF-H/M (pNF-H/M), non-phosphorylated NF-H/M (npNF-H/M) and NF-L were significantly higher (pNF-H/M, approximately 12-24-fold; npNF-H/M, approximately 3-4-fold) in neurologically healthy aged people than young control individuals; (ii), that in AD, the levels of npNF-H/M, and NF-L were similar to vascular dementia (VaD), and higher than in age-matched controls; and (iii), that the levels of pNF-H/M were significantly higher than in aged controls, non-AD neurological disorders and VaD. Based on these findings, it is suggested that the increased level of total NF proteins in CSF could be used as a marker for brain aging and neurodegenerative disorders in general, and the levels of pNF-H/M as a marker to discriminate AD from normal brain aging and as well as neurological conditions including VaD.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Encéfalo/metabolismo , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Neurônios/metabolismo , Regulação para Cima/fisiologia , Adolescente , Fatores Etários , Idoso , Encéfalo/patologia , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Imunoensaio , Masculino , Pessoa de Meia-Idade , Neurônios/patologia , Fosforilação , Proteínas tau/líquido cefalorraquidiano
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