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1.
Artigo em Inglês | MEDLINE | ID: mdl-32057367

RESUMO

Macrophage-mediated inflammation is a key pathophysiological component of cardiovascular diseases, but the underlying mechanisms by which the macrophage regulates inflammation have been unclear. In our study, we, for the first time, showed an endogenous sulfur dioxide (SO2) production in RAW267.4 macrophages by using HPLC and SO2-specific fluorescent probe assays. Moreover, the endogenous SO2 generating enzyme aspartate aminotransferase (AAT) was found to be expressed by the macrophages. Furthermore, we showed that AAT2 knockdown triggered spontaneous macrophage-mediated inflammation, as represented by the increased TNF-α and IL-6 levels and the enhanced macrophage chemotaxis; these effects could be reversed by the treatment with a SO2 donor. Mechanistically, AAT2 knockdown activated the NF-κB signaling pathway in macrophages, while SO2 successfully rescued NF-κB activation. In contrast, forced AAT2 expression reversed AngII-induced NF-κB activation and subsequent macrophage inflammation. Moreover, treatment with a SO2 donor also alleviated macrophage infiltration in AngII-treated mouse hearts. Collectively, our data suggest that macrophage-derived SO2 is an important regulator of macrophage activation and it acts as an endogenous "on-off switch" in the control of macrophage activation. This knowledge might enable a new therapeutic strategy for cardiovascular diseases.

2.
Oxid Med Cell Longev ; 2019: 1253289, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885769

RESUMO

The study was aimed at investigating the effects of L-cystathionine on vascular endothelial cell apoptosis and its mechanisms. Cultured human umbilical vein endothelial cells (HUVECs) were used in the study. Apoptosis of vascular endothelial cells was induced by homocysteine. Apoptosis, mitochondrial superoxide anion, mitochondrial membrane potential, mitochondrial permeability transition pore (MPTP) opening, and caspase-9 and caspase-3 activities were examined. Expression of Bax, Bcl-2, and cleaved caspase-3 was tested and BTSA1, a Bax agonist, and HUVEC Bax overexpression was used in the study. Results showed that homocysteine obviously induced the apoptosis of HUVECs, and this effect was significantly attenuated by the pretreatment with L-cystathionine. Furthermore, L-cystathionine decreased the production of mitochondrial superoxide anion and the expression of Bax and restrained its translocation to mitochondria, increased mitochondrial membrane potential, inhibited mitochondrial permeability transition pore (MPTP) opening, suppressed the leakage of cytochrome c from mitochondria into the cytoplasm, and downregulated activities of caspase-9 and caspase-3. However, BTSA1, a Bax agonist, or Bax overexpression successfully abolished the inhibitory effect of L-cystathionine on Hcy-induced MPTP opening, caspase-9 and caspase-3 activation, and HUVEC apoptosis. Taken together, our results indicated that L-cystathionine could protect against homocysteine-induced mitochondria-dependent apoptosis of HUVECs.

3.
Front Neurosci ; 13: 1214, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31780890

RESUMO

Purpose: To improve the metoprolol therapeutic effectiveness, we aimed to explore whether baseline heart rate variability (HRV) indicators before metoprolol treatment were useful for predicting its efficacy for postural tachycardia syndrome (POTS). Methods: We recruited 45 children with POTS who received metoprolol and 17 healthy controls. All children underwent a standing test or basic head-up tilt test and 24-h dynamic electrocardiography before treatment. After 3 months of metoprolol, therapeutic responsiveness was evaluated. The usefulness of baseline HRV parameters in predicting the effectiveness of metoprolol was studied and the long-term cumulative symptom rate was analyzed. Results: The baseline HRV frequency domain indicators for power, ultra-low frequency, very-low frequency, low frequency (LF), high frequency (HF), and total power (TP) as well as time domain indicators were significantly lower for responders than non-responders to metoprolol; however, low-frequency normalized units and LF/HF ratio were markedly greater for responders than non-responders. On series-parallel analysis, combined baseline triangular (TR) index ≤ 33.7 and standard deviation of all normal-to-normal intervals (SDNN) index ≤ 79.0 ms as cut-off values yielded sensitivity, specificity and accuracy of 85.3, 81.8, and 84.4%, respectively, to predict therapeutic responsiveness to metoprolol. On long-term follow-up, the cumulative symptom rate was significantly higher with TR index > 33.7 and SDNN index ≤ 79.0 ms, TR index ≤ 33.7 and SDNN index > 79.0 ms or TR index > 33.7 and SDNN index > 79.0 ms than TR index ≤ 33.7 and SDNN index ≤ 79.0 ms (P < 0.05). Conclusion: Combined TR index ≤ 33.7 and SDNN index ≤ 79.0 ms were useful preliminary measures to predict therapeutic response to metoprolol in pediatric POTS.

4.
J Cardiovasc Pharmacol Ther ; : 1074248419885633, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31698947

RESUMO

AIM: Vascular calcification (VC) is thought to be an independent predictor of cardiovascular morbidity and mortality. Intermedin1-53 (IMD) is a cardiovascular protective peptide and can inhibit vascular medial calcification in rats. In this study, we investigated the effect of IMD on atherosclerotic calcification induced by a high-fat diet plus homocysteine (Hcy) and the potential mechanisms. METHODS: ApoE-/- mice were fed a high-fat diet with Hcy in drinking water to induce atherosclerotic calcification. RESULTS: As compared to the high-fat diet alone, Hcy treatment significantly increased atherosclerotic lesion areas and the number of calcified nodules in aortic roots and was reduced by IMD infusion or 4-phenylbutyric acid (PBA) treatment. In vitro, as compared to calcifying medium alone, Hcy treatment further increased alkaline phosphatase activity, calcium content, and calcium nodule number in human aorta vascular smooth muscle cells (HA-VSMCs), all blocked by IMD or PBA pretreatment. Mechanistically, IMD or PBA significantly alleviated endoplasmic reticulum stress (ERS) activation compared with Hcy treatment. In parallel, IMD or PBA attenuated the messenger RNA levels of osteogenic markers and inflammatory cytokines in aortas and their protein levels in lesions of aortic roots. In vitro, Hcy treatment significantly increased the protein levels of osteoblast-like cell markers in primary rat VSMCs and inflammation markers in mouse peritoneal macrophages, all decreased with IMD or PBA pretreatment. Intermedin1-53 pretreatment also markedly reduced the protein levels of ERS markers in rat VSMCs and mouse peritoneal macrophages. CONCLUSIONS: Intermedin1-53 protects against Hcy-promoted atherosclerotic calcification in ApoE-/- mice by inhibiting ERS.

5.
Clin Sci (Lond) ; 133(20): 2045-2059, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31654061

RESUMO

BACKGROUND: Pulmonary artery endothelial cell (PAEC) inflammation is a critical event in the development of pulmonary arterial hypertension (PAH). However, the pathogenesis of PAEC inflammation remains unclear. METHODS: Purified recombinant human inhibitor of κB kinase subunit ß (IKKß) protein, human PAECs and monocrotaline-induced pulmonary hypertensive rats were employed in the study. Site-directed mutagenesis, gene knockdown or overexpression were conducted to manipulate the expression or activity of a target protein. RESULTS: We showed that hydrogen sulfide (H2S) inhibited IKKß activation in the cell model of human PAEC inflammation induced by monocrotaline pyrrole-stimulation or knockdown of cystathionine γ-lyase (CSE), an H2S generating enzyme. Mechanistically, H2S was proved to inhibit IKKß activity directly via sulfhydrating IKKß at cysteinyl residue 179 (C179) in purified recombinant IKKß protein in vitro, whereas thiol reductant dithiothreitol (DTT) reversed H2S-induced IKKß inactivation. Furthermore, to demonstrate the significance of IKKß sulfhydration by H2S in the development of PAEC inflammation, we mutated C179 to serine (C179S) in IKKß. In purified IKKß protein, C179S mutation of IKKß abolished H2S-induced IKKß sulfhydration and the subsequent IKKß inactivation. In human PAECs, C179S mutation of IKKß blocked H2S-inhibited IKKß activation and PAEC inflammatory response. In pulmonary hypertensive rats, C179S mutation of IKKß abolished the inhibitory effect of H2S on IKKß activation and pulmonary vascular inflammation and remodeling. CONCLUSION: Collectively, our in vivo and in vitro findings demonstrated, for the first time, that endogenous H2S directly inactivated IKKß via sulfhydrating IKKß at Cys179 to inhibit nuclear factor-κB (NF-κB) pathway activation and thereby control PAEC inflammation in PAH.

6.
Peptides ; 121: 170131, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31408662

RESUMO

Extensive proliferation of vascular smooth muscle cell (VSMC) contributes to intimal hyperplasia following vascular injury, in which endoplasmic reticulum stress (ERS) plays a critical role. Intermedin (IMD) is a vascular paracrine/autocrine peptide exerting numerous beneficial effects in cardiovascular diseases. IMD overexpression could alleviate intimal hyperplasia. Here, we investigated whether endogenous IMD protects against intimal hyperplasia by inhibiting endoplasmic reticulum stress. The mouse left common carotid-artery ligation-injury model was established to induce intimal hyperplasia using IMD-/-mice and C57BL/6 J wild-type (WT) mice. Platelet-derived growth factor-BB (PDGF-BB) was used to stimulate the proliferation of VSMC. IMD-/- mice displayed exacerbated intimal hyperplasia induced by complete ligation of the left carotid artery at 14 d and 28 d compared to WT mice. However, IMD-deficiency had no effect on blood pressure, plasma triglyceride, and fasting blood glucose levels in mice. Furthermore, VSMCs derived from IMD-/- mice showed increased cell proliferation and dramatically elevated levels of glucose regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), ATF6 mRNA under PDGF-BB treatment compared to WT mice-derived VSMCs. In addition, exogenous administration of IMD significantly attenuated PDGF-BB-induced cell proliferation and GRP78, phosphorylase-inositol requiring enzyme 1α, ATF4, and ATF6 protein levels. Thus, endogenous IMD may counteract ERS to exert protective role in response to vascular injury and IMD is expected to be a therapeutic target for the prevention and treatment of restenosis.

7.
Front Pediatr ; 7: 261, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31316954

RESUMO

Objectives: To explore the long-term outcomes of children and adolescents with postural tachycardia syndrome receiving conventional interventions. Materials and Methods: A total of 121 patients were recruited, but 6 (5.0%) of them were lost at follow-up. The detailed clinical data were collected, and the reoccurrence and frequency of orthostatic intolerance symptoms were evaluated with a mean followed-up period of 18.7 months (range, 14-74 months). The Kaplan-Meier curve was used to show the cumulative symptom-free rate of patients over time. Factors influencing the long-term outcomes were examined using the Cox's proportional hazards models. Results: The cumulative symptom-free rate was gradually increased over time. It was 48.4% at the 1-year follow-up and increased to 85.6% at the 6-year follow-up. The duration of symptoms before treatment and the maximum upright heart rate in standing-up test were identified as independent indicators for the long-term outcomes. Each 1-month prolongation in the duration of symptoms before treatment was associated with a 1.2% decrease in the cumulative symptom-free rate. However, each 1-bpm increase in the maximum upright heart rate in standing-up test was associated with a 2.1% increase in the cumulative symptom-free rate. Conclusions: The long-term outcomes of postural tachycardia syndrome patients who received conventional interventions are benign and the cumulative symptom-free rate was gradually increased over time. The prolonged duration of symptoms before treatment and the reduced maximum upright heart rate in standing-up test are the independent risk indicators.

8.
Biochem Biophys Res Commun ; 514(3): 907-912, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31084929

RESUMO

The interactions between vasoactive peptides and gasotransmitters have attracted considerable attention from scientists. However, the impact of angiotensin II (AngII) on the endogenous hydrogen sulfide/cystathionine γ-lyase (H2S/CSE) pathway in vascular endothelial cells remains unclear. In this study, we found, for the first time, that AngII downregulated the endogenous H2S/CSE pathway in a time-dependent manner. Mechanistically, AngII accelerated the degradation of the CSE protein and shortened its half-life in endothelial cells. AngII significantly induced Lys48 (K48)-linked CSE ubiquitination and subsequent CSE degradation but did not affect Lys63 (K63)-linked CSE ubiquitination in vascular endothelial cells. Treatment with the proteasome inhibitor MG132 and mutation of Lys48 to Arg in ubiquitin successfully blunted the inhibitory effects of AngII on the endogenous H2S/CSE pathway in vascular endothelial cells. Furthermore, we found that superoxide anion levels were significantly increased in AngII-treated endothelial cells compared with controls and that the ROS scavenger N-acetyl-l-cysteine (NAC) significantly abolished CSE ubiquitination. Taken together, our data suggested that AngII inhibited endogenous H2S generation through ubiquitination-mediated CSE degradation via the ROS pathway in vascular endothelial cells.

10.
Front Pharmacol ; 10: 313, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30971931

RESUMO

Sulfur dioxide (SO2) is a colorless and irritating gas. Recent studies indicate that SO2 acts as the gas signal molecule and inhibits vascular smooth muscle cell (VSMC) proliferation. Cell proliferation depends on intracellular pH (pHi). Transmembrane cystein mutation of Na+- independent Cl-/HCO3 - exchanger (anion exchanger, AE) affects pHi. However, whether SO2 inhibits VSMC proliferation by reducing pHi is still unknown. Here, we investigated whether SO2 reduced pHi to inhibit the proliferation of VSMCs and explore its molecular mechanisms. Within a range of 50-200 µM, SO2 was found to lower the pHi in VSMCs. Concurrently, NH4Cl pre-perfusion showed that SO2 significantly activated AE, whereas the AE inhibitor 4,4'-diisothiocyanatostilbene- 2,20-disulfonic acid (DIDS) significantly attenuated the effect of SO2 on pHi in VSMCs. While 200 µM SO2 sulphenylated AE2, while dithiothreitol (DTT) blocked the sulphenylation of AE2 and subsequent AE activation by SO2, thereby restoring the pHi in VSMCs. Furthermore, DIDS pretreatment eliminated SO2-induced inhibition of PDGF-BB-stimulated VSMC proliferation. We report for the first time that SO2 inhibits VSMC proliferation in part by direct activation of the AE via posttranslational sulphenylation and induction of intracellular acidification.

11.
Front Pediatr ; 7: 81, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941338

RESUMO

Objective: We evaluated the ability of peripheral blood neutrophil-to-lymphocyte ratio (NLR) to predict the intravenous immunoglobulin (IVIG) resistance in Kawasaki disease (KD) patients under 1-year of age. Methods: A total of 92 KD patients under the age of 1-year and who were hospitalized in Peking University First Hospital from June 2007 to August 2016 were recruited in this study. The clinical and laboratory data were analyzed to see if peripheral blood NLR was useful for predicting the IVIG-resistance in KD. Results: Totally 81 out of 92 patients were IVIG responders while 11 resistant to IVIG, with no significant difference in age, gender, ratio of the number of the incomplete to the number of complete KD, and the number of patients with coronary artery lesion between two groups (p > 0.05). Peripheral blood NLR was increased significantly in IVIG-resistant children compared to the IVIG responders [2.6 (interquartile range: 1.4, 3.8) vs. 1.7 (interquartile range: 0.9, 2.3), p = 0.039]. A cut-off value of NLR of 2.51 in KD patients younger than 1-year old yielded a sensitivity of 0.545 and specificity of 0.840, respectively, in the prediction of IVIG resistance. An area under the curve of 0.692 (95% confidence interval 0.526-0.859, p = 0.039) was determined. Conclusions: The peripheral blood NLR ≥ 2.51 is useful to predict the IVIG resistance in KD patients younger than 1-year old.

12.
Chin Med J (Engl) ; 132(4): 411-419, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30707176

RESUMO

BACKGROUND: Vasovagal syncope (VVS) is common in children and greatly affect both physical and mental health. But the mechanisms have not been completely explained. This study was designed to analyze the gut microbiota in children with VVS and explore its clinical significance. METHODS: Fecal samples from 20 VVS children and 20 matched controls were collected, and the microbiota were analyzed by 16S rRNA gene sequencing. The diversity and microbiota compositions of the VVS cases and controls were compared with the independent sample t test or Mann-Whitney U test. The correlation between the predominant bacteria and clinical symptoms was analyzed using Pearson or Spearman correlation test. RESULTS: No significant differences in diversity were evident between VVS and controls (P > 0.05). At the family level, the relative abundance of Ruminococcaceae was significantly higher in VVS children than in controls (median [Q1, Q3]: 22.10% [16.89%, 27.36%] vs. 13.92% [10.31%, 20.18%], Z = -2.40, P < 0.05), and LEfSe analysis revealed Ruminococcaceae as a discriminative feature (linear discriminant analysis [LDA] score > 4, P < 0.05). The relative abundance of Ruminococcaceae in VVS patients was positively correlated with the frequency of syncope (r = 0.616, P < 0.01). In terms of its correlation with hemodynamics, we showed that relative abundance of Ruminococcaceae was negatively correlated with the systolic and diastolic pressure reduction at the positive response in head-up tilt test (HUTT; r = -0.489 and -0.448, all P < 0.05), but was positively correlated with the mean pressure drop and decline rate (r = 0.489 and 0.467, all P < 0.05) as well as diastolic pressure drop and decline rate at the HUTT positive response (r = 0.579 and 0.589, all P < 0.01) in VVS patients. CONCLUSION: Ruminococcaceae was the predominant gut bacteria and was associated with the clinical symptoms and hemodynamics of VVS, suggesting that gut microbiota might be involved in the development of VVS.


Assuntos
Microbioma Gastrointestinal , Síncope Vasovagal/microbiologia , Adolescente , Criança , Pré-Escolar , Ácidos Graxos Voláteis/metabolismo , Feminino , Humanos , Masculino , Ruminococcus/isolamento & purificação , Ruminococcus/fisiologia , Síncope Vasovagal/etiologia
13.
J Cell Physiol ; 234(10): 17578-17588, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30793300

RESUMO

Cardiac hypertrophy is the main cause of heart failure and sudden death in patients. But the pathogenesis is unclear. Angiotensin II may contribute to cardiac hypertrophy in response to pressure overload. In angiotensin II-treated cardiomyocytes, there is a larger cross-sectional area, more apoptosis cells, and a reduction of irisin expression. An increase in P62, an autophagy flux index, as well as LC3II, were observed in cardiomyocytes after angiotensin II-induced injury. Surprisely, irisin supplementation increased LC3II expression and decreased P62 expression, consisted of results of RFP-GFP-LC3B adenovirus transfection, and reduced cardiomyocyte apoptosis, meanwhile, the protection of irisin was reversed by the autophagy inhibitor 3-methyladenine. In animal experiments, overexpression of irisin reduced cardiomyocyte apoptosis and alleviated myocardial hypertrophy caused by pressure overload. The above results indicate that irisin-induced protective autophagy and alleviated the apoptosis signaling pathway in cardiomyocytes, consequently reducing cardiomyocyte apoptosis after angiotensin II-induced injury. Hence, increasing irisin expression may be a new way to improve cardiac function and quality of life in patients with cardiac hypertrophy.

14.
J Pediatr ; 207: 54-58, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30528576

RESUMO

OBJECTIVE: To explore the value of the acceleration index as a predictor of therapeutic response to orthostatic training in children with vasovagal syncope (VVS). STUDY DESIGN: Thirty-three children with VVS were recruited and treated with orthostatic training. The therapeutic response of each patient was evaluated after 3 months of treatment. A Pearson correlation was calculated between the acceleration index and the severity of VVS. The value of the acceleration index in predicting the therapeutic response to orthostatic training was assessed by analysis of the receiver operating characteristic curve. RESULTS: Among the 33 children with VVS, 20 were found to be responders and the remaining were nonresponders. The mean acceleration index was significantly lower in responders compared with nonresponders (21.10 ± 6.61 vs 31.36 ± 9.00; P = .001) and it was negatively correlated with positive response time in the head-up tilt test, with systolic blood pressure and with diastolic blood pressure at positive response time in the head-up tilt test (P < .05). The receiver operating characteristic curve for the predictive value of the acceleration index showed that the area under the curve was 0.827 (95% CI, 0.676-0.978; P = .002), and a cutoff value of the acceleration index of 26.77 yielded a sensitivity of 85.0% and a specificity of 69.2%. CONCLUSIONS: The acceleration index may be useful for predicting the efficacy of orthostatic training on VVS in children.

15.
Antioxid Redox Signal ; 30(2): 184-197, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29343087

RESUMO

Aims: Hydrogen sulfide (H2S) has a protective role in the pathogenesis of atherosclerosis by multiple pathways. Sirtuin-1 (SIRT1) is a histone deacetylase, as an essential mediated longevity gene, and has an anti-atherogenic effect by regulating the acetylation of some functional proteins. Whether SIRT1 is involved in protecting H2S in atherosclerosis and its mechanism remains unclear. Results: In ApoE-knockout atherosclerosis mice, treatment with an H2S donor (NaHS or GYY4137) reduced atherosclerotic plaque area, macrophage infiltration, aortic inflammation, and plasma lipid level. H2S treatment increased aorta and liver SIRT1 mRNA expression. Overexpression or slicing cystathionine gamma lyase (CSE) also changed intracellular SIRT1 expression. CSE/H2S treatment increased SIRT1 deacetylation in endothelium and hepatocytes and macrophages, then induced deacetylation of its target proteins (P53, P65, and sterol response element binding protein), thereby reducing endothelial and macrophage inflammation and inhibiting macrophage cholesterol uptake and cholesterol de novo synthesis of liver. Also, CSE/H2S induced SIRT1 sulfhydration at its two zinc finger domains, increased its zinc ion binding activity to stabilize the alpha-helix structure, lowered its ubiquitination, and reduced its degradation. Innovation: H2S is a novel SIRT1 activator by direct sulfhydration. Because SIRT1 has a role in longevity, H2S may be a protector for aging-related diseases. Conclusion: Endogenous CSE/H2S directly sulfhydrated SIRT1, enhanced SIRT1 binding to zinc ion, then promoted its deacetylation activity, and increased SIRT1 stability, thus reducing atherosclerotic plaque formation.

16.
Int Heart J ; 60(1): 45-49, 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30393265

RESUMO

Neuregulin-4 (Nrg4) is a newly discovered adipokine that is synthesized in many tissues and plays an important role in modulating systemic energy metabolism and in the development of metabolic disorders. However, little is known about the relationship between Nrg4 and coronary artery disease (CAD). In this study, we investigated the association between Nrg4 and the presence and severity of CAD.We enrolled 73 patients diagnosed by coronary angiography (CAG) as having CAD and 32 controls. The CAD group was divided into two subgroups according to their SYNTAX score. Plasma levels of Nrg4 were measured in all participants and compared among different groups. The relationship between Nrg4 and CAD was analyzed. Receiver operating characteristic (ROC) analysis was conducted to evaluate the usefulness Nrg4 in assessing the presence and severity of CAD.Nrg4 levels were negatively associated with the SYNTAX score (r = -0.401, P = 0.000). The patients with a higher SYNTAX score had significantly lower Nrg4 levels as compared with the low SYNTAX score subgroup and the controls (P < 0.05). The Nrg4 levels of the low SYNTAX score subgroup were much lower than controls (P < 0.05). Furthermore, an association between Nrg4 and CAD (odds ratio, 0.279; 95% confidence interval, 0.088-0.882) was observed. Nrg4 had 43.8% sensitivity and 96.9% specificity for identifying CAD, and 73.1% sensitivity and 87.3% specificity for identifying patients who had severe coronary artery lesions.Nrg4 levels were found to be inversely associated with the presence and severity of CAD.


Assuntos
Biomarcadores/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Neurregulinas/sangue , Idoso , Estudos de Casos e Controles , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade , Índice de Gravidade de Doença
17.
Front Pediatr ; 6: 375, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30560108

RESUMO

The study was designed to evaluate the changes of plasma homocysteine (Hcy) level in children with postural tachycardia syndrome (POTS) and explore its significance. A total of 65 subjects were recruited in our study, of whom 35 children were in the POTS group and 30 healthy children were in the control group. Plasma Hcy levels were determined in all subjects. The relationship between the plasma Hcy level and the symptom score was analyzed in the 35 POTS patients. The relationship between the plasma Hcy level and the change in heart rate from the supine to upright position (ΔHR) and between the plasma Hcy level and the rate of increase in heart rate from the supine to upright position (ΔHR/sHR × 100%) were analyzed in all subjects. The plasma Hcy levels were significantly higher in the children with POTS than those in the control group (9.78 [7.68, 15.31] µmol/L vs. 7.79 [7.46, 9.63] µmol/L, P < 0.05). The plasma Hcy levels were positively correlated with symptom scores in the POTS patients (n = 35, r = 0.522, P < 0.01). The plasma Hcy levels were also positively correlated with ΔHR (n = 65, r = 0.332, P < 0.01) and ΔHR/sHR × 100% (n = 65, r = 0.341, P < 0.01) in all the subjects. In conclusion, the plasma Hcy levels were elevated in the children with POTS positively correlated with the severity of POTS, suggesting that Hcy might be involved in the pathogenesis of POTS.

18.
Front Pediatr ; 6: 343, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30510926

RESUMO

Objectives: To explore the predictive value of immediate heart rate alteration from supine to upright in the differential diagnosis between vasovagal syncope (VVS) and postural tachycardia syndrome (POTS) in children. Materials and Methods: A total of 76 pediatric outpatients or inpatients who visited the Peking University First Hospital from July 2016 to November 2017 were recruited in the study. Among them, 52 patients were diagnosed with VVS and 24 patients were diagnosed with POTS. The differential diagnostic value of acceleration index (AI) and 30/15 ratio was evaluated by the receiver operating characteristic (ROC) curve. An external validation test was performed in another 46 patients. Results: Compared with the cases in the VVS group, patients in the POTS group had a significantly increased AI but a decreased 30/15 ratio (33.495 ± 8.472 vs. 23.440 ± 8.693, p < 0.001; 0.962 ± 0.067 vs. 1.025 ± 0.084, p = 0.002; respectively). The ROC curves showed that AI and 30/15 ratio were useful for differentiating POTS from VVS. A cut-off value of AI set at 28.180 yielded a sensitivity of 79.2% and a specificity of 73.1%. A cut-off value of 30/15 ratio set at 1.025 yielded a sensitivity of 87.5% and a specificity of 61.5%. A combined use of these two indices improved the sensitivity to 95.8% when either AI or 30/15 was used, and specificity to 80.8% with the use of both AI and 30/15 at the same diagnosis. The external validation test showed that the positive and negative predictive values of the AI and 30/15 ratio were 77.3 and 79.2%, and 72.0 and 81.0%, respectively. The positive predictive value increased to 87.5% when both the AI and 30/15 ratio cut-off values were used together. Conclusions: The AI and 30/15 ratio, which are easy to perform and non-invasive, have proper sensitivity and specificity to differentiate patients with POTS from those with VVS. The combination of these two indices significantly improves the predictive value.

19.
J Mol Cell Cardiol ; 121: 242-255, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30053525

RESUMO

In hypertrophic hearts, autophagic flux insufficiency is recognized as a key pathology leading to maladaptive cardiac remodeling and heart failure. This study aimed to illuminate the cardioprotective role and mechanisms of a new myokine and adipokine, irisin, in cardiac hypertrophy and remodeling. Adult male wild-type, mouse-FNDC5 (irisin-precursor)-knockout and FNDC5 transgenic mice received 4 weeks of transverse aortic constriction (TAC) alone or combined with intraperitoneal injection of chloroquine diphosphate (CQ). Endogenous FNDC5 ablation aggravated and exogenous FNDC5 overexpression attenuated the TAC-induced hypertrophic damage in the heart, which was comparable to the protection of irisin against cardiomyocyte hypertrophy induced by angiotensin II (Ang II) or phenylephrine (PE). Accumulated autophagosome and impaired autophagy flux occurred in the TAC-treated myocardium and Ang II- or PE-insulted cardiomyocytes. Irisin deficiency caused reduced autophagy and aggravated autophagy flux failure, whereas irisin overexpression or supplementation induced protective autophagy and improved autophagy flux, which were reversed by autophagy inhibitors Atg5 siRNA, 3-MA and CQ. Irisin boosted the activity of only AMPK but not Akt and MAPK family members in hypertrophic hearts and cultured cardiomyocytes and further activated ULK1 at Ser555 but not Ser757 and did not affect the mTOR-S6K axis. Blockage of AMPK and ULK1 with compund C and SBI-0206965, respectively, both abrogated irisin's protection against cardiomyocyte hypertrophic injury and reversed its induction of both autophagy and autophagy flux. Our results suggest that irisin protects against pressure overload-induced cardiac hypertrophy by inducing protective autophagy and autophagy flux via activating AMPK-ULK1 signaling.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Cardiomegalia/genética , Fibronectinas/genética , Insuficiência Cardíaca/genética , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Angiotensina II/administração & dosagem , Animais , Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/antagonistas & inibidores , Benzamidas/administração & dosagem , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/patologia , Humanos , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/efeitos dos fármacos , Fenilefrina/administração & dosagem , Pressão , Pirimidinas/administração & dosagem , Transdução de Sinais , Serina-Treonina Quinases TOR/genética
20.
Chin Med J (Engl) ; 131(14): 1715-1723, 2018 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-29998892

RESUMO

Background: Myocardial fibrosis is an important pathological change in many heart diseases, but its pathogenesis is very complex and has not yet been fully elucidated. The study was designed to examine whether endogenous sulfur dioxide (SO2) is a novel myocardial fibroblast proliferation and migration inhibitor. Methods: Primary rat myocardial fibroblasts were isolated and transfected with aspartate aminotransferase (AAT1 and AAT2) knockdown lentivirus or empty lentivirus. SO2 content in the supernatant was determined with high-performance liquid chromatography, and the expressions of AAT1, AAT2, proliferating cell nuclear antigen (PCNA), phosphorylated extracellular signal-regulated protein kinase (p-ERK), and total ERK (T-ERK) in the cells were detected. Cell migration was detected by wound healing test. Independent sample t-test (for two groups) and one-way analysis of variance (three or more groups) were used to analyze the results. Results: Both AAT1 and AAT2 knockdown significantly reduced SO2levels (F = 31.46, P < 0.01) and AAT1/2 protein expression (AAT1, t = 12.67, P < 0.01; AAT2, t = 9.61, P < 0.01), but increased PCNA expression and Cell Counting Kit-8 (CCK-8) activity as well as the migration in rat primary myocardial fibroblasts (P < 0.01). Supplementation of SO2rather than pyruvate significantly inhibited the increase in proliferation and migration caused by AAT knockdown (P < 0.01). Mechanistically, the ratio of p-ERK to T-ERK was significantly increased in the AAT1/2 knockdown groups compared with that in the empty lentivirus group (AAT1, t = -7.36, P < 0.01; AAT2, t = -10.97, P < 0.01). Whereas PD98059, an inhibitor of ERK activation, successfully blocked AAT knockdown-induced PCNA upregulation (F = 74.01, P > 0.05), CCK-8 activation (F = 50.14, P > 0.05), and migration augmentation in myocardial fibroblasts (24 h, F = 37.08, P > 0.05; 48 h, F = 58.60, P > 0.05). Conclusion: Endogenous SO2might be a novel myocardial fibroblast proliferation and migration inhibitor via inhibiting the ERK signaling pathway.


Assuntos
Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dióxido de Enxofre/farmacologia , Animais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos , Ratos , Transdução de Sinais
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