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1.
J Cell Mol Med ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32022386

RESUMO

Th22 cells are a novel subset of CD4+ T cells that primarily mediate biological effects through IL-22, with both Th22 cells and IL-22 being closely associated with multiple autoimmune and chronic inflammatory diseases. In this study, we investigated whether and how Th22 cells affect atherosclerosis. ApoE-/- mice and age-matched C57BL/6J mice were fed a Western diet for 0, 4, 8 or 12 weeks. The results of dynamic analyses showed that Th22 cells, which secrete the majority of IL-22 among the known CD4+ cells, play a major role in atherosclerosis. ApoE-/- mice fed a Western diet for 12 weeks and administered recombinant mouse IL-22 (rIL-22) developed substantially larger plaques in both the aorta and aortic root and higher levels of CD3+ T cells, CD68+ macrophages, collagen, IL-6, Th17 cells, dendritic cells (DCs) and pSTAT3 but lower smooth muscle cell (SMC) α-actin expression than the control mice. Treatment with a neutralizing anti-IL-22 monoclonal antibody (IL-22 mAb) reversed the above effects. Bone marrow-derived DCs exhibited increased differentiation into mature DCs following rIL-22 and ox-LDL stimulation. IL-17 and pSTAT3 were up-regulated after stimulation with IL-22 and ox-LDL in cells cocultured with CD4+ T cells and mature DC supernatant, but this up-regulation was significantly inhibited by IL-6mAb or the cell-permeable STAT3 inhibitor S31-201. Thus, Th22 cell-derived IL-22 aggravates atherosclerosis development through a mechanism that is associated with IL-6/STAT3 activation, DC-induced Th17 cell proliferation and IL-22-stimulated SMC dedifferentiation into a synthetic phenotype.

2.
Life Sci ; 245: 117338, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31981630

RESUMO

Secreted frizzled-related protein 5 (Sfrp5) primarily acts in combination with wingless-type family member 5a (Wnt5a), to inhibits chronic inflammation and repress atherosclerosis and other metabolic disorders. Epicardial adipose tissue (EAT), surrounding the heart and coronary arteries, has been found to be highly related to the progression of coronary artery disease through adipokines production. However, little is known about EAT-derived Sfrp5 and Wnt5a in humans. We aimed to investigate whether the EAT-derived Sfrp5/Wnt5a levels are altered in patients with CAD. Fifty-eight patients with CAD and 29 patients without CAD who underwent cardiac surgery were enrolled. Serum samples and paired adipose biopsies from EAT and subcutaneous adipose tissue (SAT) were collected, and Sfrp5 and Wnt5a levels were detected. Correlation and multivariate regression analyses were performed to determine the relationship between Sfrp5/Wnt5a expression and CAD and other clinical risk factors. According to the results, the CAD group had lower Sfrp5 and higher Wnt5a levels in EAT and serum (all p < 0.05). Serum Sfrp5 levels were significantly lower in CAD patients with impaired myocardial function. EAT Sfrp5 mRNA levels and serum Sfrp5 levels were both negatively associated with the presence of CAD, after adjustment for known biomarkers, EAT mRNA and serum Wnt5a levels correlated positively with the presence of CAD. Thus, we concluded that low Sfrp5 and high Wnt5a levels are associated with the presence of CAD, independent of other conventional risk factors.

3.
Aging (Albany NY) ; 12(1): 193-203, 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31901899

RESUMO

Our previous studies have demonstrated that interleukin-12p35 knockout (IL-12p35 KO) regulates the progression of various cardiovascular diseases, such as acute cardiac injury and hypertension. The aims of this study were to investigate whether IL-12p35 KO affects aging-related cardiac remodeling and to explore the possible mechanisms. First, the effects of IL-12p35 KO on heart structure and function were detected, and the results showed that IL-12p35 KO exacerbated cardiac remodeling and increased cardiac senescence-related protein levels in aged mice. In addition, whether IL-12p35 KO regulates cardiac senescence-related protein expression, cardiac mitochondrial dysfunction and cardiomyocyte apoptosis was also investigated. IL-12p35 KO increased mitochondrial calcium fluorescence intensity and ROS fluorescence intensity, while it reduced mitochondrial membrane potential. Furthermore, reduced mitochondrial complex (I-IV) activity and ATP levels and increased apoptosis-inducing factor (AIF)-related cardiomyocyte apoptosis were observed in aged IL-12p35 KO mice compared with wild-type mice. Our results demonstrate that aging is aggravated by IL-12p35 KO and that the mechanism may be related to exacerbation of mitochondrial dysfunction and AIF-related cardiomyocyte apoptosis.

4.
Medicine (Baltimore) ; 98(50): e18241, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852089

RESUMO

T helper 17 (Th17) cells are related to the progression of aortic dissection. This study aimed to determine whether circulating Th17 levels are associated with the prognosis of acute Stanford type B aortic dissection (STBAD) after thoracic endovascular aortic repair (TEVAR).A cohort study was performed and STBAD patients (n = 140) received TEVAR were enrolled, the circulating Th17 levels were measured and the patients were divided into low and high Th17 groups, and 36 months of follow-up was performed. The data for mortality, survival outcomes, heart structure and function changes, aortic regurgitation prevalence, and aortic remodeling outcomes were recorded.Lower mortality and fewer complications were observed in the low Th17 group than in the high Th17 group in the third year of follow-up. In addition, the low Th17 group exhibited better cardiac remodeling and cardiac function when compared with that in the high Th17 group in the second to third year after TEVAR. Aortic reflux was improved in both groups but was more pronounced in the low Th17 group. During follow-up, the true lumen of the proximal thoracic aorta at the level of the celiac trunk in both the low and high Th17 groups continuously enlarged and was more pronounced in the low Th17 group.Circulating Th17 cells were related to cardiac and aortic remodeling and prognosis during STBAD after TEVAR. Anti-inflammatory therapy may be useful for STBAD patients who have undergone TEVAR.


Assuntos
Aneurisma Dissecante/sangue , Aorta Torácica/cirurgia , Aneurisma da Aorta Torácica/sangue , Procedimentos Endovasculares/métodos , Células Th17/patologia , Remodelação Vascular , Doença Aguda , Adulto , Aneurisma Dissecante/diagnóstico , Aneurisma Dissecante/cirurgia , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/fisiopatologia , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/cirurgia , Angiografia por Tomografia Computadorizada , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Retrospectivos , Fatores de Tempo
5.
Lipids Health Dis ; 18(1): 131, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31153370

RESUMO

OBJECTIVE: Familial hypercholesterolemia (FH) is an important cause of premature coronary artery disease (CAD). Prognosis data are lacking in patients with FH and coronary artery disease particularly in the era of widespread statin use. We compared long-term prognosis between patients with and without FH after a coronary event. METHODS: In this retrospective study, 865 patients younger than 40 years of age with CAD were enrolled. FH was diagnosed based on the Dutch Lipid Clinic Network algorithm. Baseline characteristics, coronary angiographic findings and prognosis during median follow-up of 5 (3-8) years were compared between patients with or without FH. RESULTS: Definite or probable FH was detected in 37 patients (4.3%) and possible FH in 259 patients (29.9%). FH was associated with significantly higher prevalence of multi-vessel lesions (p < 0.001) and higher Gensini score (p = 0.008). In the subset of 706 patients for whom follow-up data were available, 127 (18.0%) suffered major adverse cardiovascular and cerebrovascular events (MACCE). FH was associated with increased risk of MACCE, independently of age, sex, smoking, body mass index, hypertension or diabetes mellitus (HR = 2.30, 95%CI = 1.09 to 4.84, p = 0.028). CONCLUSIONS: FH is an independent risk factor for MACCE in young patients after a coronary event during long-term follow-up. It is necessary to optimize lipid treatment of patients with FH after a coronary event.


Assuntos
Doença da Artéria Coronariana/diagnóstico , Hiperlipoproteinemia Tipo II/diagnóstico , Intervenção Coronária Percutânea/efeitos adversos , Prognóstico , Adolescente , Adulto , Índice de Massa Corporal , LDL-Colesterol/sangue , Angiografia Coronária , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/patologia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/patologia , Feminino , Humanos , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/diagnóstico por imagem , Hiperlipoproteinemia Tipo II/patologia , Hipertensão/complicações , Hipertensão/epidemiologia , Hipertensão/patologia , Masculino , Fatores de Risco , Caracteres Sexuais , Fumar/efeitos adversos , Adulto Jovem
6.
J Interferon Cytokine Res ; 39(8): 472-482, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31199714

RESUMO

Adipose tissue stores energy and is the largest endocrine organ in the body, producing several adipokines. However, among these adipokines, few play a role in the positive metabolism that promotes good health. Secreted frizzled-related protein (Sfrp)-5, an antagonist that directly binds to Wnt, has attracted interest due to its favorable effects on atherosclerotic cardiovascular disease (ASCVD). This review focuses on Sfrp5 biology and the roles of the Sfrp5/Wnt system in ASCVD.

7.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(10): 1338-1349, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31125703

RESUMO

Mature dendritic cells (DCs) play a pathogenic role in atherosclerosis. Our previous study demonstrated that exogenous interleukin (IL)-37 suppresses the maturation of DCs, induces the T-regulatory (Treg) cell response, and attenuates atherosclerosis in ApoE-/- mice. The aim of the present study was to explore the molecular mechanism of IL-37 on the maturation of DCs throughout the development of atherosclerosis. The expression of interleukin-1 receptor 8 (IL-1R8), which is a single Ig-domain receptor that was recently found to be pivotal for the extracellular function of IL-37, Toll-like receptor (TLR) 4 and p65, was measured in ApoE-/- mice and IL-37 transgenic (IL-37tg) ApoE-/- mice. IL-1R8 was mainly expressed in aortic plaque-infiltrated DCs and at significantly higher levels in IL-37tg atherosclerotic mice, accompanied by lower levels of TLR4 and p65. Furthermore, IL-37 eliminated the maturation of DCs induced by oxidized low-density lipoprotein (oxLDL) and caused marked upregulation of IL-1R8 in vitro and downregulation of TLR4 and p65, which was consistent with the experiments in mice. However, the inhibitory effect of IL-37 on the maturation of DCs in vitro was abolished when IL-37 was used to treat DCs isolated from IL-1R8-deficient and TLR4-deficient mice. Therefore, this study indicated that IL-37 inhibited the maturation of DCs via the IL-1R8-TLR4-NF-κB pathway and attenuated atherosclerosis in ApoE-/- mice.

8.
Life Sci ; 230: 104-110, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31128138

RESUMO

BACKGROUND: Previous studies have demonstrated that type 2 diabetes mellitus (T2DM) is negatively correlated with the occurrence of aortic dissection (AD). This study aimed to investigate the effects of T2DM on the prognosis of Stanford type B AD (STBAD) patients after thoracic endovascular aortic repair (TEVAR). METHODS: STBAD patients (n = 141) who underwent TEVAR received an oral glucose tolerance test (OGTT) and were divided into a normal glucose (NG, n = 55) group, an abnormal glucose tolerance (AGT, n = 48) group and a T2DM (n = 38) group according to the results of the OGTT. Data on mortality, clinical complications, left ventricular (LV) remodeling and aortic remodeling were collected during the 3-year follow-up. RESULTS: Lower mortality and fewer clinical complications after TEVAR were found in the T2DM group than in the NG group. Multivariate linear regression analysis showed that 2-hour postprandial glucose (Glu-2h) was negatively correlated with mortality and the occurrence of clinical complications in STBAD patients after TEVAR. In addition, better LV remodeling, larger true lumen areas and smaller false lumen areas in both the proximal aortas and abdominal aortas were observed in the T2DM group than in the NG group. Furthermore, no significant differences in mortality or clinical complications after TEVAR were found between the NG group and the AGT group or between the T2DM group and the AGT group. CONCLUSION: During the 3-year follow-up period, mortality and clinical complications in STBAD patients after TEVAR were significantly reduced in the T2DM group. For STBAD patients who undergo TEVAR, properly relaxing of blood glucose control requirements may be beneficial for their prognosis.


Assuntos
Aneurisma Dissecante/fisiopatologia , Aorta Torácica/cirurgia , Adulto , Idoso , Aneurisma Dissecante/mortalidade , Aneurisma Dissecante/cirurgia , Aorta Abdominal/fisiopatologia , Aorta Torácica/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Seguimentos , Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Remodelação Vascular
9.
Mediators Inflamm ; 2019: 3152040, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31093011

RESUMO

Interleukin- (IL-) 35, a novel functional cytokine of regulatory T cells (Treg) comprised of the IL-12p35 subunit and the other subunit Epstein-Barr virus-induced gene 3 (EBI3), regulates the activity of CD4+ T cells and macrophages, thereby playing a critical role in inflammatory and autoimmune diseases. Previous studies demonstrated that both recombinant mice and human IL-35 attenuated atherosclerosis in ApoE-/- mice. Additionally, EBI3 deficiency enhanced the activation of macrophages and increased atherosclerotic lesions in LDLR-/- mice. This study generated double-deficient mice for ApoE and IL-12p35 (ApoE-/- IL-12p35-/- mice) and investigated the effect of IL-12p35 deficiency on atherosclerosis. IL-12p35 deficiency alleviated Th1/Th2 imbalance, aggravated Th17/Treg imbalance, and attenuated atherosclerotic plaque formation in ApoE-/- mice. Additionally, exogenous rIL-35 treatment reversed the imbalance of Th17/Treg and attenuated atherosclerosis in ApoE-/- mice. These findings suggest that IL-12p35 deficiency ameliorates atherosclerosis in ApoE-/- mice, partially, via attenuating the Th1/Th2 imbalance, although IL-12p35 deficiency aggravates the Th17/Treg imbalance.


Assuntos
Subunidade p35 da Interleucina-12/metabolismo , Células Th1/metabolismo , Células Th2/metabolismo , Animais , Apolipoproteínas E , Aterosclerose/imunologia , Aterosclerose/metabolismo , Imuno-Histoquímica , Interleucina-10/metabolismo , Subunidade p35 da Interleucina-12/deficiência , Interleucina-4/metabolismo , Masculino , Camundongos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo
10.
Mediators Inflamm ; 2019: 1575410, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30728748

RESUMO

Background: Interleukin-11 (IL-11) is an important inflammatory cytokine and has been demonstrated to participate in cardiovascular diseases. However, there have been no studies about the role of IL-11 in heart failure (HF). The present study is aimed at investigating whether IL-11 levels are associated with the cardiac prognosis in patients with HF. Methods: The plasma concentrations of IL-11 were measured in 240 patients with chronic HF (CHF) and 80 control subjects without signs of significant heart disease. In addition, we prospectively followed these CHF patients to endpoints of cardiac events. Results: Compared with the control group, the plasma IL-11 concentrations were significantly increased in the CHF patients and gradually increased in the New York Heart Association (NYHA) functional class II group, the NYHA functional class III group, and the NYHA functional class IV group. The receiver operating characteristic (ROC) curve revealed that the predictive role of IL-11 in HF is not as good as N-terminal B-type natriuretic peptide (BNP), although IL-11 has a certain value in predicting cardiac events. In addition, the CHF patients were divided into 3 groups according to the plasma IL-11 concentration category (low, T1; middle, T2; and high, T3). The multivariate Cox hazard analysis showed that the high plasma IL-11 concentrations were independently associated with the presence of cardiac events after adjustment for confounding factors. Furthermore, the CHF patients were divided into two groups based on the median plasma IL-11 concentrations. The Kaplan-Meier analysis revealed that the patients with high IL-11 concentrations had a higher risk of cardiac events compared with those with low IL-11 concentrations. Conclusions: Higher plasma IL-11 levels significantly increase the presence of cardiac events and suggest a poor outcome; although the diagnostic value of IL-11 in CHF is not as good as BNP, there is a certain value in predicting cardiac events in CHF.


Assuntos
Insuficiência Cardíaca/sangue , Interleucina-11/sangue , Adulto , Idoso , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/complicações , Estudos de Casos e Controles , Doença Crônica , Citocinas/metabolismo , Ecocardiografia , Feminino , Seguimentos , Insuficiência Cardíaca/complicações , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Alta do Paciente , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Curva ROC , Função Ventricular Esquerda
11.
J Atheroscler Thromb ; 26(10): 868-878, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30773518

RESUMO

AIM: Several members of secreted frizzled-related protein (SFRP) are involved in the process of myocardial ischemia-reperfusion injury. However, little is known about the role of SFRP5 in patients with acute ST-segment elevation myocardial infarction (STEMI). METHODS: In this cross-sectional study, 85 patients with first-time anterior STEMI who underwent timely primary percutaneous coronary intervention (PCI) and 35 patients without coronary artery disease (CAD) were enrolled. Serum SFRP5 levels were measured using an enzyme-linked immunosorbent assay kit. Patients with STEMI were divided into low-SFRP5 and high-SFRP5 groups according to their median baseline serum SFRP5 levels. To evaluate cardiac function and structure after infarction, the left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume (LVEDV) were measured using echocardiography. The associations between changes in LVEF and reduced LVEF (≤ 50%) and clinical variables were determined by univariate and multivariate analyses. RESULTS: Baseline serum SFRP5 levels were significantly higher in patients with STEMI than in those without CAD (23.3 ng/mL vs 19.8 ng/mL, P=0.008), although they decreased over time. Also, baseline serum SFRP5 levels were inversely correlated with peak hypersensitive cardiac troponin I (hs-cTnI) levels (r=-0.234, P=0.025) and peak hypersensitive C-reactive protein (hs-CRP) levels (r=-0.262, P=0.015). A multivariate linear regression model showed that changes in LVEF were positively correlated with serum SFRP5 levels at baseline (ß= 0.249, 95% confidence interval (CI) 0.018-0.245, P=0.024) and 24 h after admission (ß=0.220, 95% CI 0.003-0.264, P=0.045). At 3 months, LVEF in patients with high SFRP5 levels was significantly improved over baseline [(60.8±7.1) % vs (56.1±7.5) %, P=0.001]. LVEF was also significantly higher in patients with high SFRP5 levels than in those with low at the 3-month follow-up [(60.8±7.1) % vs (56.8±8.9) %, P=0.028]. Consequently, high serum SFRP5 levels at baseline were associated with a decreased risk of reduced LVEF at 3 months, independent of peak hs-cTnI and baseline cardiac function (hazard ratio 0.190, 95% CI 0.036-0.996; P=0.049). CONCLUSIONS: High serum SFRP5 levels measured during the acute phase of STEMI were significantly associated with promoting myocardial recovery at an early phase following primary PCI, suggesting that SFRP5 is a potential therapeutic target in acute STEMI.

12.
Angiology ; 70(5): 423-430, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30343583

RESUMO

This study aimed to investigate the favorable revascularization threshold for fractional flow reserve (FFR) in daily practice. Between March 2013 and March 2017 in a high-volume center in China, 903 patients with 1210 lesions underwent coronary intervention with adjunctive FFR and were consecutively enrolled. The mean FFR was 0.80 ± 0.11, revascularization was deferred for 68% of lesions, and the median follow-up period was 21 months. For lesions with an FFR > 0.80, deferral of revascularization appeared safe. In contrast, for lesions with an FFR ≤ 0.80, deferral of revascularization was associated with a greater risk of target lesion failure (TLF) than revascularization (hazard ratio [HR] 4.63, 95% confidence interval [CI] 2.02-10.06, P < .001). For lesions with an FFR value in the gray-zone (0.76-0.80), medical treatment alone was less effective than revascularization ( P = .020). For deferred lesions, FFR was an independent predictor for the future risk of TLF, when data were categorized (HR [FFR ≤ 0.75 vs FFR ≥ 0.86] 3.35, 95% CI 1.13-9.97, P = .030; HR [FFR 0.76-0.80 vs FFR ≥ 0.86] 4.01, 95% CI 1.73-9.31, P = .001) or continuous (HR 0.004, 95% CI 0.00-0.13, P = .002). Thus, an FFR value of 0.80 appears to be the optimal threshold for decision-making regarding revascularization and risk stratification.


Assuntos
Cateterismo Cardíaco , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/cirurgia , Reserva Fracionada de Fluxo Miocárdico , Hospitais com Alto Volume de Atendimentos , Intervenção Coronária Percutânea , Idoso , China , Tomada de Decisão Clínica , Angiografia Coronária , Doença da Artéria Coronariana/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Valor Preditivo dos Testes , Fatores de Risco , Fatores de Tempo , Tempo para o Tratamento , Resultado do Tratamento
13.
Cardiovasc Res ; 115(6): 1102-1113, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30395167

RESUMO

AIMS: Numerous studies have demonstrated that inflammation is involved in the progression of hypertension. Inflammatory cytokines interleukin (IL)-12 and IL-35 belong to the IL-12 cytokine family and share the same IL-12p35 subunit. Accumulating evidence has demonstrated that IL-12p35 knockout (IL-12p35 KO) leads to cardiovascular disease by regulating the inflammatory response. This study aimed to investigate whether IL-12p35 KO elevates blood pressure in a hypertension mouse model. METHODS AND RESULTS: Mice with angiotensin (Ang) II infusion showed marked aortic IL-12p35 expression; thus, aortic macrophages may be the main source of IL-12p35. Wild-type and IL-12p35 KO mice were infused with Ang II or saline. IL-12p35 KO promoted M1 macrophage differentiation, amplified the inflammatory response, aggravated vascular dysfunction, and elevated blood pressure in Ang II-treated mice. Then, some Ang II-infused mice were given phosphate buffer saline, mouse recombinant IL-12 (rIL-12), or rIL-35, and the results showed that rIL-12 but not rIL-35 treatment had an antihypertensive effect on Ang II-infused mice. In addition, detection of human plasma IL-12 levels in hypertensive patients and control subjects showed that IL-12 was significantly increased in hypertensive patients when compared with control subjects. In hypertensive patients, IL-12 levels were positively correlated with blood pressure. CONCLUSION: IL-12p35 KO amplifies the inflammatory response and promotes blood pressure elevation in Ang II-treated mice. In addition, IL-12, but not IL-35, plays a protective role in the Ang II-induced hypertension model. Thus, IL-12 may be a novel therapeutic agent for the prevention and treatment of clinical hypertension.

14.
Life Sci ; 218: 132-138, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30594664

RESUMO

BACKGROUND: Previous studies have demonstrated that oxidative stress is closely related to aortic dissection (AD). Sestrin2 (Sesn2) is an important antioxidant protein, and this study aimed to investigate whether Sesn2 participates in AD and the possible mechanisms. METHODS: Sesn2 expression was detected in aortas collected from AD patients and normal donors. In addition, blood samples were collected from AD patients and non-AD (NAD) patients, and the plasma Sesn2 levels were measured. Furthermore, the effects of Sesn2 on angiotensin (Ang) II-induced smooth muscle cell (SMC) apoptosis were investigated in vitro. RESULTS: Compared with the aortas from normal donors, aortas from AD patients had significantly increased Sesn2. Sesn2 was mainly secreted by macrophages, and low levels were secreted by CD4+ T lymphocytes, but not SMCs. Plasma Sesn2 levels were also increased in AD patients compared with NAD patients. Sesn2 levels were negatively corrected with superoxide dismutase (SOD) levels but positively corrected with malondialdehyde (MDA) levels in AD patients. In co-cultures of macrophages and SMCs, Sesn2 overexpression in macrophages significantly reduced Ang II-induced SMC apoptosis, and this effect could be reversed by Nrf2 silencing. CONCLUSIONS: Sesn2 is increased in both aortas and plasma from AD patients. Sesn2 may alleviate Ang II-induced SMC apoptosis and participate in AD via the Nrf2 pathway. Sesn2 may be a new target in the treatment and prevention of AD.


Assuntos
Angiotensina II/farmacologia , Aorta/patologia , Doenças da Aorta/patologia , Apoptose , Miócitos de Músculo Liso/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Nucleares/metabolismo , Aneurisma Dissecante , Aorta/efeitos dos fármacos , Aorta/metabolismo , Doenças da Aorta/metabolismo , Doenças da Aorta/cirurgia , Biomarcadores/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Fator 2 Relacionado a NF-E2/genética , Proteínas Nucleares/genética , Estresse Oxidativo , Vasoconstritores/farmacologia
15.
EBioMedicine ; 35: 29-39, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30228093

RESUMO

BACKGROUND: Recent evidence has demonstrated that interleukin 12p35 knockout (IL-12p35 KO) is involved in cardiac diseases by regulating the inflammatory response. The involvement of inflammatory cells has also been observed in doxorubicin (DOX)-induced cardiac injury. This study aimed to investigate whether IL-12p35 KO affects DOX-induced cardiac injury and the underlying mechanisms. METHODS: First, the effect of DOX treatment on cardiac IL-12p35 expression was assessed. In addition, to investigate the effect of IL-12p35 KO on DOX-induced cardiac injury, IL-12p35 KO mice were treated with DOX. Because IL-12p35 is the mutual subunit of IL-12 and IL-35, to determine the cytokine that mediates the effect of IL-12p35 KO on DOX-induced cardiac injury, mice were given phosphate-buffered saline (PBS), mouse recombinant IL-12 (rIL-12) or rIL-35 before treatment with DOX. RESULTS: DOX treatment significantly increased the level of cardiac IL-12p35 expression. In addition, IL-12p35 KO mice exhibited higher serum and heart lactate dehydrogenase levels, higher serum and heart creatine kinase myocardial bound levels, and greater cardiac dysfunction than DOX-treated mice. Furthermore, IL-12p35 KO further increased M1 macrophage and decreased M2 macrophage differentiation, aggravated the imbalance of oxidants and antioxidants, and further activated the mitochondrial apoptotic pathway and endoplasmic reticulum stress autophagy pathway. Both rIL-12 and rIL-35 protected against DOX-induced cardiac injury by alleviating the inflammatory response, oxidative stress, apoptosis and autophagy. CONCLUSIONS: IL-12p35 KO aggravated DOX-induced cardiac injury by amplifying the levels of inflammation, oxidative stress, apoptosis and autophagy. (234 words).


Assuntos
Apoptose , Autofagia , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/fisiopatologia , Doxorrubicina/efeitos adversos , Inflamação/patologia , Subunidade p35 da Interleucina-12/deficiência , Estresse Oxidativo , Animais , Apoptose/efeitos dos fármacos , Autofagossomos/metabolismo , Autofagossomos/ultraestrutura , Autofagia/efeitos dos fármacos , Biomarcadores/metabolismo , Cardiotônicos/metabolismo , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Subunidade p35 da Interleucina-12/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/patologia , Miocárdio/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo
16.
Mediators Inflamm ; 2018: 5697149, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30258282

RESUMO

Background: Previous studies demonstrated that the subsets of CD4+ T helper (Th) cells are closely related to vascular diseases, including atherosclerosis and hypertension. This study is aimed at investigating the circulating Th1, Th2, Th9, Th17, Th22, and Treg levels in aortic dissection (AD) patients. Methods: Blood samples from AD (n = 56) and non-AD (NAD, n = 24) patients were collected, and the circulating levels of Th1, Th2, Th9, Th17, Th22, and Treg cells and their transcription factors and functional cytokines were measured by flow cytometric analysis, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assays, respectively. In addition, the human aortic vascular smooth muscle cells (HASMCs) were treated with saline, angiotensin II (Ang II), or plasma from AD patients. Results: Compared with the levels in the NAD group, the Th1, Th9, Th17, Th22, and their transcription factor levels were increased and the Th2, Treg, and their transcription factor levels exhibited a decreasing trend in AD patients. In addition, higher IFN-γ, IL-9, IL-17, and IL-22 levels and lower IL-4 and IL-35 levels were observed in AD patients. Simple linear regression analysis and binary logistic regression analysis suggested that Th1/IFN-γ, IL-9, Th17/IL-17, and Th22/IL-22 positively regulated the occurrence of AD, while Th2/IL-4 and Treg/IL-35 negatively regulated the occurrence of AD. Plasma from AD patients further increased Bax mRNA levels but decreased Bcl2 and α-SMA mRNA levels in Ang II-treated HASMCs. Conclusions: Changes in Th1, Th2, Th9, Th17, Th22, and Treg activity are associated with the onset of AD. Different subsets of CD4+ T cells play different roles in the presence of AD.


Assuntos
Aneurisma Dissecante/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th1/metabolismo , Células Th17/metabolismo , Células Th2/metabolismo , Apoptose/fisiologia , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Interleucina-17/metabolismo , Interleucina-4/metabolismo , Interleucina-9/metabolismo , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade
19.
Clin Chim Acta ; 486: 177-182, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30086263

RESUMO

Aortic dissection (AD) is one of the most dangerous forms of vascular disease, characterized by endometrial rupture and intramural hematoma formation. Generally, the pathological process is complicated and closely related to the infiltration of inflammatory cells into the aortic wall and apoptosis of vascular smooth muscle cells. Currently, multiple cytokines, including interleukins, interferon, the tumor necrosis factor superfamily, colony stimulating factor, chemotactic factor, growth factor and so on, have all been demonstrated to play a critical role in AD. Additionally, studies of the link between cytokines and AD could deepen our understanding of the disease and may guide future treatment therapies; therefore, this review focuses on the role of cytokines in AD.


Assuntos
Aneurisma Dissecante/metabolismo , Citocinas/metabolismo , Aneurisma Dissecante/tratamento farmacológico , Aneurisma Dissecante/patologia , Animais , Apoptose , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia
20.
Clin Chim Acta ; 481: 193-199, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29555322

RESUMO

BACKGROUND: Interleukin (IL) 11 is closely related to tumor and hematological system diseases. Recent studies have demonstrated that IL-11 also participates in cardiovascular diseases, including ischemia-reperfusion mediated heart injury and acute myocardial infarction. This study aimed to investigate whether IL-11 is involved in acute thoracic aortic dissection (TAD). METHODS: Aortic tissue samples from normal donors and acute TAD patients were collected, and the expression of IL-11 in all aortic tissue was analyzed. In addition, blood samples from patients with chest pain were collected and divided into a non-AD (NAD) group and a TAD group according to the results of computed tomography angiography of the thoracic aorta. The plasma IL-11, IL-17 and interferon (IFN) γ in all blood samples were measured. RESULTS: Compared with aortic tissue of normal controls, IL-11 was significantly increased in aortic tissue of acute TAD patients, especially in the torn section. The IL-11 was derived from aorta macrophages in TAD. In addition, the plasma IL-11, IL-17 and IFN-γ were significantly higher in acute TAD patients than in NAD patients, and the correlation analysis showed that IL-11 levels were positively correlated with levels of IFN-γ, IL-17, glucose, systolic blood pressure, diastolic blood pressure, white blood cells, C-reactive proteins and D-dimers. Binary logistic regression analyses showed that elevated IL11 in patients who may have diagnostic value of TAD, but less that D-dimer. CONCLUSION: IL-11 was increased in thoracic aorta and plasma of TAD patients and may be a promising biomarker for diagnosis in patients with TAD.


Assuntos
Aneurisma Dissecante/sangue , Aneurisma Dissecante/diagnóstico , Aorta Torácica/química , Aneurisma da Aorta Torácica/sangue , Interleucina-11/sangue , Adulto , Idoso , Aneurisma da Aorta Torácica/diagnóstico , Feminino , Humanos , Interleucina-11/biossíntese , Masculino , Pessoa de Meia-Idade , Análise de Regressão
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