RESUMO
Endothelia inflammation damage is vital to the development and progression of chronic venous disease. In the present study, we explored the protective effect of melatonin on endothelia apoptosis induced by LPS, particularly focusing on the mitochondrial fission. We demonstrated that human umbilical vein endothelial cells (HUVEC) subjected to LPS for 12 h exhibited a higher apoptotic rate. However, melatonin (1-20 µM) treatment 12 h before LPS had the ability to protect HUVEC cell against LPS-mediated apoptosis in a dose-dependent manner. Furthermore, LPS induced the cytoplasmic calcium overload which was responsible for the upregulation of calcium-dependent xanthine oxidase (XO). Higher XO expression was associated with reactive oxygen species (ROS) overproduction, leading to the Drp1 phosphorylation at the Ser616 site and migration on the surface of mitochondria. Furthermore, phosphorylated Drp1 initiated the mitochondrial fission contributing to the caspase9-dependent mitochondrial apoptosis as evidenced by lower membrane potential, more cyt-c leakage into the nuclear, and higher expression of proapoptotic proteins. However, melatonin treatment could trigger the AMPK pathway, which was followed by the increased SERCA2a expression. Activation of AMPK/SERCA2a by melatonin inhibited the calcium overload, XO-mediated ROS outburst, Drp1-required mitochondrial fission, and final mitochondrial apoptosis. In summary, this study confirmed that LPS induced HUVEC apoptosis through Ca2+-XO-ROS-Drp1-mitochondrial fission axis and that melatonin reduced the apoptosis of HUVEC through activation of the AMPK/SERCA2a pathway.
Assuntos
Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Inflamação/patologia , Melatonina/farmacologia , Dinâmica Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Adenilato Quinase/metabolismo , Caspase 9/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lipopolissacarídeos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Regulação para Cima/efeitos dos fármacos , Xantina Oxidase/metabolismoRESUMO
Angiotensin II (Ang II) has been reported as key in inducing endothelial cell injury, and endothelial cells may produce nitric oxide (NO) to protect themselves. However, the underlying mechanism remains elusive. Human umbilical vein endothelial cells (HUVECs) were divided into five treatment groups as follows: Normal control, Ang II, Ang II + sodium hydrosulfide [NaHS; hydrogen sulfide (H2S) donor], Ang II + Akt inhibitors + NaHS, and Ang II + endothelial nitric oxide synthases (eNOS) inhibitors + NaHS. Subsequently, cell viability, apoptosis, migration, proliferation and adhesion ability were determined. In addition, tubular structure formation was observed, and the NO and phosphorylation levels of Akt and eNOS were evaluated. Compared with the normal control group, Ang II treatment reduced the viability of HUVECs and increased the level of cell apoptosis (P<0.05). Furthermore, Ang II treatment inhibited the phosphorylation level of eNOS and Akt, as well as the generation of NO (P<0.05). H2S reversed the abovementioned effects significantly and increased cell proliferation, adhesion ability and promoted tubular structure formation (P<0.05); however, H2S did not reverse the impact of eNOS and Akt phosphorylation levels after being processed with Akt and eNOS inhibitors, which indicates that H2S is capable of protecting HUVECs via the eNOS/Akt signaling pathway (P<0.05). Thus, H2S stimulates the production of NO and protects HUVECs via inducing the Akt/eNOS signaling pathway.
Assuntos
Angiotensina II/farmacologia , Sulfeto de Hidrogênio/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hidrogênio/metabolismo , Fosforilação/efeitos dos fármacosRESUMO
To perform a meta-analysis and examine the use of D-dimer levels for diagnosing acute aortic dissection (AAD). Medline, Cochrane, EMBASE, and Google Scholar were searched until April 23, 2014, using the following search terms: biomarker, acute aortic dissection, diagnosis, and D-dimer. Inclusion criteria were diagnosis of acute aortic dissection, D-dimer levels obtained, 2-armed study. Outcome measures were the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of D-dimer level for the diagnosis of AAD. Sensitivity analysis was performed using the leave-one-out approach. Of 34 articles identified, 5 met the inclusion criteria and were included in the analysis. The age of participants was similar between treatments within studies. The number of AAD patients ranged from 16 to 107 (totalâ=â274), and the number of control group patients ranged from 32 to 206 (totalâ=â469). The pooled sensitivity of D-dimer levels in AAD patients was 94.5% (95% confidence interval [CI] 78.1%-98.8%, Pâ<â0.001), and the specificity was 69.1% (95% CI 43.7%-86.5%, Pâ=â0.136). The pooled area under the receiver-operating characteristic curve for D-dimer levels in AAD patients was 0.916 (95% CI 0.863-0.970, Pâ<â0.001). The direction and magnitude of the combined estimates did not change markedly with the exclusion of individual studies, indicating the meta-analysis had good reliability. D-dimer levels are best used for ruling out AAD in patients with low likelihood of the disease.
Assuntos
Aneurisma Aórtico/diagnóstico , Dissecção Aórtica/diagnóstico , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Dissecção Aórtica/sangue , Aneurisma Aórtico/sangue , Biomarcadores/sangue , Humanos , Valor Preditivo dos Testes , Sensibilidade e EspecificidadeRESUMO
We report a recent case and review some literatures of acute aortic dissection (AAD) Stanford type B complicated with late onset of acute renal failure. The patient underwent preoperational peritoneal dialysis followed by thoracic endovascular aortic repair (TEVAR) and was fully recovered and discharged soon after surgery. We conclude that an AAD case is difficult to achieve a timely diagnosis, but with attention to systemic symptoms and dedication thorough treatment plan, a full recovery and positive prognosis are expected.