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1.
Circ Rep ; 3(2): 86-94, 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33693294

RESUMO

Background: Atherosclerosis is an inflammatory disease involving activation of adaptive and innate immune responses to antigens, including oxidized low-density lipoprotein (oxLDL) and phosphorylcholine (PC). Dendritic cells (DCs), which are antigen-presenting cells that activate T cells, are present in atherosclerotic lesions and are activated in immune organs. However, the mechanism by which PC promotes atherosclerosis is unclear. Methods and Results: To evaluate whether PC promotes atherosclerosis via DCs, 2×105 DCs activated by PC-keyhole limpet hemocyanin (DCs+PC-KLH) were injected into ApoE-/- mice and the features of the plaques and the effects of the DCs on cellular and humoral immunity against PC-KLH were determined. Mice injected with DCs+PC-KLH had significantly larger atherosclerotic lesions than controls, with increased inflammation in the lesions and plaque instability. Furthermore, DCs+PC-KLH were characterized using flow cytometry after coculture of bone marrow-derived DCs and naïve T cells. DCs+PC-KLH showed an inflammatory phenotype, with increased CD86, CD40, and major histocompatibility complex Class II molecules (MHC-II), which promoted PC-specific T helper (Th) 1 and Th17 cell differentiation in vivo and in vitro. Moreover, 2 weeks after the administration of DCs+PC-KLH to mice, these mice produced PC- and oxLDL-specific IgG2a, compared with no production in the controls. Conclusions: These findings suggest that DCs presenting PC promote specific immunity to PC, increase lesion inflammation, and accelerate atherosclerosis, which may explain how PC promotes atherosclerosis.

2.
Oxid Med Cell Longev ; 2020: 1645249, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32256945

RESUMO

Oxidative stress and subsequent cardiac myocyte apoptosis play central roles in the initiation and progression of myocardial ischemia-reperfusion (I/R) injury. Homeobox transcript antisense intergenic RNA (Hotair) was previously implicated in various heart diseases, yet its role in myocardial I/R injury has not been clearly demonstrated. Mice with cardiac-restricted knockdown or overexpression of Hotair were exposed to I/R surgery. H9c2 cells were cultured and subjected to hypoxia/reoxygenation (H/R) stimulation to further verify the role and underlying mechanisms of Hotair in vitro. Histological examination, molecular detection, and functional parameters were determined in vivo and in vitro. In response to I/R or H/R treatment, Hotair expression was increased in a bromodomain-containing protein 4-dependent manner. Cardiac-restricted knockdown of Hotair exacerbated, whereas Hotair overexpression prevented I/R-induced oxidative stress, cardiac myocyte apoptosis, and cardiac dysfunction. Mechanistically, we observed that Hotair exerted its beneficial effects via activating AMP-activated protein kinase alpha (AMPKα). Further detection revealed that Hotair activated AMPKα through regulating the enhancer of zeste homolog 2/microRNA-451/calcium-binding protein 39 (EZH2/miR-451/Cab39) axis. We provide the evidence that endogenous lncRNA Hotair is an essential negative regulator for oxidative stress and cardiac myocyte apoptosis in myocardial I/R injury, which is dependent on AMPKα activation via the EZH2/miR-451/Cab39 axis.


Assuntos
Traumatismo por Reperfusão Miocárdica/genética , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/genética , RNA Longo não Codificante/metabolismo , Animais , Apoptose , Masculino , Camundongos
3.
PLoS One ; 9(2): e88775, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24558424

RESUMO

OBJECTIVE: CD4(+) latency-associated peptide (LAP)(+) regulatory T cells (Tregs) are a newly discovered T cell subset in humans and the role of these cells in patients with acute coronary syndrome (ACS) has not been explored. We designed to investigate whether circulating frequency and function of CD4(+)LAP(+) Tregs are defective in ACS. METHODS: One hundred eleven ACS patients (acute myocardial infarction and unstable angina) and 117 control patients were enrolled in the study. The control patients consisted of chronic stable angina (CSA) and chest pain syndrome (CPS). The frequencies of circulating CD4(+)LAP(+) Tregs and the expression of the transmembrane protein glycoprotein-A repetitions predominant (GARP) on CD4(+) T cells were determined by flow cytometry. The function of CD4(+)LAP(+) Tregs was detected using thymidine uptake. Serum interleukin-10 (IL-10) and transforming growth factor-ß protein (TGF-ß) levels were detected using ELISA and expression of GARP mRNA in peripheral blood mononuclear cells (PBMCs) was measured by real time-polymerase chain reaction. RESULTS: We found ACS patients had a significantly lower frequency of circulating CD4(+)LAP(+) Tregs, and the function of these cells was reduced compared to controls. The expression of GARP in CD4(+) T cells and the serum levels of TGF-ß in ACS patients were lower than those of control patients. The serum levels of IL-10 were similar between the two cohorts. CONCLUSIONS: A novel regulatory T cell subset, defined as CD4(+)LAP(+) T cells is defective in ACS patients.


Assuntos
Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/imunologia , Linfócitos T Reguladores/citologia , Síndrome Coronariana Aguda/genética , Angina Estável/sangue , Angina Estável/imunologia , Dor no Peito/sangue , Dor no Peito/imunologia , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Crescimento Transformador beta1/sangue
4.
Biol Pharm Bull ; 36(2): 268-75, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23196655

RESUMO

Imatinib mesylate (IM), a widely prescribed powerful tyrosine kinase inhibitor, has been associated with increased risk of heart failure and is known to induce cell apoptosis and death in isolated cardiomyocytes. In addition to acquired long QT syndrome, pharmacological inhibition of human ether-à-go-go-related gene (HERG) channel has been reported to involve in apoptosis. The present study was undertaken to characterize the biophysical properties of IM on HERG and the molecular determinants of HERG blockade using mutant channels (Y652A and F656A). Wild type (WT) and mutant HERG channels were expressed in HEK-293 cells and Xenopus oocytes and the currents (I(HERG)) were measured using patch-clamp and two-microelectrode voltage-clamp techniques. IM inhibited WT I(HERG) in a concentration-dependent manner with an IC(50) of 19.51±2.50 µmol/L and 44.76±1.54 µmol/L in HEK-293 cells and Xenopus oocytes, respectively. The IM-induced inhibition of WT I(HERG) followed a voltage- and time-dependent manner. The blockade was enhanced by further activation of currents, which were in accordance with an open-channel blockade. The V(1/2) for steady-state activation shifted from -15.48±1.21 to -26.66±2.98 mV (p<0.05, n=6). The inactivation kinetics and voltage dependence of steady-state inactivation of the WT HERG channel were not significantly altered by IM. Two S6 domain mutants, F652A and Y656A, attenuated IM-induced inhibition of WT I(HERG). Therefore, IM preferentially blocked the open HERG channel through F652 and Y656, providing a molecular mechanism for the cardiac side effects during the clinical administration of IM.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Piperazinas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Células Cultivadas , Canais de Potássio Éter-A-Go-Go/fisiologia , Células HEK293 , Humanos , Mesilato de Imatinib , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Xenopus
5.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-275704

RESUMO

<p><b>OBJECTIVE</b>To study the frequency distribution in polymorphism of the apoprotein B 3' variable number tandem repeat (ApoB3'VNTR) and influence factors on hyperlipemia in civil aircrew.</p><p><b>METHODS</b>ApoB genotypes were determined by PCR technology and agarose gel electrophoresis. The blood lipids were measured by routine kits. Personal information of flight personnel was collected by questionnaire.</p><p><b>RESULTS</b>Prevalence of the total dyslipidemia (49.5%) and overweight (55.6%) of flight personnel were much higher than that of domestic general population (29.2% and 49.1%) respectively (P < 0.05). There were 16 alleles and 54 kinds of genotypes of ApoB3'VNTR in the 682 flight personnel. The frequency distribution of alleles and genotypes of aircrew in the two air companies had same trend, which was different from the general population. The frequency of the homozygote was 76.54%, which was much higher than that of the other peoples home and abroad (21.50%). The frequency of the big allele (VNTR > or =39) in hyperlipemia groups were higher than that of normal groups. By analysis of co-variance, the body mass index (BMI), low density lipoprotein (LDL) and the total cholesterol(TC) increased with the cumulate flight hours (P < 0.05). In multivariate logistic regression analysis, the BMI was the only factor influencing blood lipids, and the cumulate flight hours was only factors affecting the BMI. Taking the cumulate flight hours logarithm as the independent variable(X), and the BMI as dependent variable(Y), the linearity equations was: Y = 2.730X + 13.584 (R2 = 0.159, P < 0.01).</p><p><b>CONCLUSION</b>There are perhaps special genetic characteristics in the polymorphism of the ApoB3'VNTR in the aircrew. The big allele is correlated with the hyperlipemia. The flight burden not only directly affects the BMI and blood lipids levels, but also it can indirectly affect the lipids levels by BMI.</p>


Assuntos
Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Apolipoproteínas B , Genética , Aviação , Índice de Massa Corporal , Colesterol , Sangue , Genótipo , Hiperlipidemias , Epidemiologia , Genética , Lipoproteínas LDL , Sangue , Repetições Minissatélites , Polimorfismo de Nucleotídeo Único
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