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1.
Cardiovasc Res ; 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31397837

RESUMO

AIMS: Circular RNAs (circRNAs) are involved in gene regulation in a variety of physiological and pathological processes. The present study aimed to investigate the effect of circRNA_000203 on cardiac hypertrophy and the potential mechanisms involved. METHODS AND RESULTS: CircRNA_000203 was found to be upregulated in the myocardium of Ang-II-infused mice and in the cytoplasma of Ang-II-treated neonatal mouse ventricular cardiomyocytes (NMVCs). Enforced-expression of circRNA_000203 enhances cell size and expression of atrial natriuretic peptide (ANP) and ß-myosin heavy chain (MHC) in NMVCs. In vivo, heart function was impaired and cardiac hypertrophy was aggravated in Ang-II-infused myocardium-specific circRNA_000203 transgenic mice (Tg-circ203). Mechanistically, we found that circRNA_000203 could specifically sponge miR-26b-5p, -140-3p in NMVCs. Further, dual luciferase reporter assay showed that miR-26b-5p, -140-3p could interact with 3'UTRs of Gata4 gene, and circRNA_000203 could block the above interactions. Additionally, Gata4 expression is transcriptionally inhibited by miR-26b-5p, -140-3p mimic in NMVCs, but enhanced by over-expression of circRNA_000203 in vitro and in vivo. Functionally, miR-26b-5p, -140-3p, and Gata4 siRNA, could reverse the hypertrophic growth in Ang-II-induced NMVCs, as well as eliminate the pro-hypertrophic effect of circRNA_000203 in NMVCs. Furthermore, we demonstrated that NF-κB signaling mediates the upregulation of circRNA_000203 in NMVCs exposed to Ang-II treatment. CONCLUSIONS: Our data demonstrated that circRNA_000203 exacerbates cardiac hypertrophy via suppressing miR-26b-5p and miR-140-3p leading to enhanced Gata4 levels.

3.
BMJ Open ; 9(5): e028007, 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31147367

RESUMO

OBJECTIVES: There are country and regional variations in the prevalence of hyperuricaemia (HUA). The prevalence of HUA and non-valvular atrial fibrillation (NVAF) in southern China is unknown. DESIGN: A cross-sectional study. SETTING AND PARTICIPANTS: A total of 11 488 permanent residents aged 35 or older from urban and rural areas of Guangzhou, China were enrolled. A questionnaire was used to compile each participant's demographic information and relevant epidemiological factors for HUA and NVAF. All participants were assessed using a panel of blood tests and single-lead 24-hour ECG. MAIN OUTCOME MEASURES: HUA was defined as serum uric acid level >420 µmol/L in men and >360 µmol/L in women. NVAF was diagnosed as per guidelines. RESULTS: The prevalence of HUA was 39.6% (44.8% in men and 36.7% in women), and 144 residents (1.25%) had NVAF. Prevalence of HUA increased with age in women but remained stably high in men. After adjusting for potential confounders, age, living in urban areas, alcohol consumption, central obesity, elevated fasting plasma glucose level, elevated blood pressure, lower high-density lipoprotein cholesterol level and elevated triglycerides level were associated with increased risk of HUA. Residents with HUA were at higher risk for NVAF. Serum uric acid level had a modest predictive value for NVAF in women but not men. CONCLUSIONS: HUA was highly prevalent among citizens of southern China and was a predictor of NVAF among women.

4.
BMC Cardiovasc Disord ; 19(1): 90, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30987582

RESUMO

BACKGROUND: The ECG characteristics of the distal coronary venous system ventricular arrhythmias (VAs) share common features with VAs arising from the aortic cusps or the endocardial left ventricular outflow tract (LVOT) beneath the cusps. The purpose of this study was to identify specific electrocardiographic and electrophysiological characteristics of VAs originating from the distal great cardiac vein (GCV). METHODS: Based on the successful ablation site, patients with idiopathic VAs from the distal GCV, left coronary cusp (LCC) or the subvalvular left ventricular outflow tract (LVOT) area were included in the present study. RESULTS: The final population consisted of 39 patients (35 males, mean age 51 ± 23 years). All VAs displayed a right bundle branch block (RBBB) morphology with inferior axis. Among these patients, 15 were successfully ablated at the GCV, 15 at the LCC and 9 at the subvalvular region. A "w" pattern in lead I was present in 12 out of 15 (80%) VAs originating from the distal GCV compared to none of VAs arising from the other two sites (p < 0.01). VAs with a GCV origin exhibited more commonly increased intrinsicoid deflection time, higher maximum deflection index and wider QRS duration compared to LCC and subvalvular sites (p < 0.05). Acceptable pace mapping at the successful ablation site was achieved in 10 patients. After an average of 36 ± 24 months follow up, 14 (93.3%) patients were free from VAs recurrence. CONCLUSION: A "w" pattern in lead I may distinguish distal GCV VAs from VAs arising from the LCC or the subvalvular region.

5.
Environ Sci Technol ; 53(5): 2509-2517, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30758964

RESUMO

The retention of polyvinyl chloride (PVC) microplastics in sewage sludge during wastewater treatment raises concerns. However, the effects of PVC microplastics on methane production from anaerobic digestion of waste activated sludge (WAS) have never been documented. In this work, the effects of PVC microplastics (1 mm, 10-60 particles/g TS) on anaerobic methane production from WAS were investigated. The presence of 10 particles/g TS of PVC microplastics significantly ( P = 0.041) increased methane production by 5.9 ± 0.1%, but higher levels of PVC microplastics (i.e., 20, 40, and 60 particles/g TS) inhibited methane production to 90.6 ± 0.3%, 80.5 ± 0.1%, and 75.8 ± 0.2% of the control, respectively. Model-based analysis indicated that PVC microplastics at >20 particles/g TS decreased both methane potential (B0) and hydrolysis coefficient (k) of WAS. The mechanistic studies showed that bisphenol A (BPA) leaching from PVC microplastics was the primary reason for the decreased methane production, causing significant ( P = 0.037, 0.01, 0.004) inhibitory effects on the hydrolysis-acidification process. The long-term effects of PVC microplastics revealed that the microbial community was shifted in the direction against hydrolysis-acidification and methanation. In conclusion, PVC microplastic caused negative effects on WAS anaerobic digestion through leaching the toxic BPA.


Assuntos
Cloreto de Polivinila , Esgotos , Anaerobiose , Compostos Benzidrílicos , Reatores Biológicos , Metano , Fenóis , Plásticos , Eliminação de Resíduos Líquidos
6.
Heart Vessels ; 34(5): 860-867, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30599061

RESUMO

To investigate the safety and midterm outcome of concomitant left atrial appendage (LAA) closure and catheter ablation (CA) as a one-stage hybrid procedure for non-valvular atrial fibrillation (AF) in a multicenter registry. A total of 50 consecutive patients with symptomatic drug-resistant non-valvular AF with CHA2DS2-VASc score ≥ 2 and contraindications for antithrombotic therapy were included in the prospectively established LAA closure registry, and underwent concomitant LAA closure (48 for WATCHMAN and 2 for ACP) and CA procedure (40 for radiofrequency and 10 for cryoballoon CA). Two cardiac tamponades, one peripheral vascular complications and one mild air embolism were observed during perioperative period. After mean follow-up of 20.2 ± 11.5 months, 18 (36%) patients presented with atrial arrhythmia relapse and 45 (91.8%) patients presented with complete sealing; furthermore, there were two transient ischemic attacks and one ischemic stroke under an off-oral anticoagulant situation, respectively. Concomitant CA and LAA closure as a one-stage hybrid procedure might be feasible and potentially decrease costs in patients with symptomatic non-valvular AF with high stroke risk and contraindication to antithrombotic treatment, and as safe as LAA closure procedure only during the perioperative period. However, it was necessary to further validate the mid-term safety.


Assuntos
Apêndice Atrial/cirurgia , Fibrilação Atrial/cirurgia , Ablação por Cateter , Dispositivo para Oclusão Septal , Idoso , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Ecocardiografia Transesofagiana , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores de Tempo , Resultado do Tratamento
7.
Int J Cancer ; 144(12): 3099-3110, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30537104

RESUMO

To investigate immune profile consisting of stromal PD-L1 expression, inhibitory or non-T-cell inflamed tumor microenvironment that may predict response to anti-PD-L1/PD-1 immunotherapy in prostate cancer, we validated the specificity of a PD-L1 monoclonal antibody (E1L3N) and identified PD-L1 specific expression in prostatic stromal nerve cells. PD-L1 expression was analyzed in 73 primary prostate cancers and 7 castration-resistant prostate cancers (CRPC) by immunohistochemistry (IHC) and resulting data from primary prostate cancers were correlated with tumor-associated lymphocytes (TALs), clinicopathological characteristics and clinical outcome. PD-L1 was expressed in the tumor cells in only one primary prostate cancer case and none of the CRPC. However, PD-L1 was frequently observed in the nerve branches in the tumor-associated stroma (69 of 73 cases, 94.5%), supported by colocalization with axonal marker PGP9.5. FoxP3-, CD3- and CD8-positive T lymphocytes were observed in 74.6% (47/63), 98.4% (62/63) and 100% (61/61) of the cases, respectively. The density of PD-L1+ tumor-associated nerves (TANs) was inversely correlated with that of CD8+ TALs. Higher density of PD-L1+ TANs was significantly associated with biochemical recurrence (BCR) in Kaplan-Meier survival analysis (p = 0.016). In both univariate and multivariate Cox analysis, the density of PD-L1+ TANs was independently prognostic of BCR. In conclusion, PD-L1 expression is rare in prostate tumor cells but prevalent in TANs and negatively correlated with CD8+ TALs. Neuro-immunological interaction may be a contribution to immune-suppressive microenvironment. Combinatorial treatment regimen designs to neural PD-L1 and TALs should be warranted in future clinical application of anti-PD-L1/PD-1 immunotherapy in prostate cancer.


Assuntos
Antígeno B7-H1/biossíntese , Linfócitos T CD8-Positivos/imunologia , Próstata/inervação , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias da Próstata/imunologia , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/cirurgia , Microambiente Tumoral/imunologia , Ubiquitina Tiolesterase
8.
Int Heart J ; 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30518718

RESUMO

The incidence of atrial tachycardia (AT) after rheumatic mitral valvular (RMV) surgery has been well described. However, there have been few reports on the characteristics, mechanism, and long-term ablation outcome of ATs after RMV surgery and concomitant Cox-MAZE IV procedure.The present study reviewed consecutive patients who underwent AT ablation between May 2008 and July 2013. All patients were refractory to antiarrhythmic drugs (AADs) and had a history of RMV surgery and Cox-MAZE IV procedure. A total of 34 patients underwent AT ablation after RMV surgery and concomitant Cox-MAZE IV procedure, and presented 57 mappable and 2 unmappable ATs. The 57 mappable ATs included 14 focal-ATs and 43 reentry-ATs. Ten of the 14 focal-like ATs were located at the pulmonary vein (PV) antrum and border of a box lesion. Of the 43 reentry-ATs, 16 were marco-reentrant around the mitral annulus (MA) and 16 around the tricuspid annulus. There were 41 atypical ATs (non-cavotricuspid isthmus related) including 16 ATs related to the box lesion and 21 ATs related to other Cox-MAZE IV lesions. The AT were successfully terminated in 33 (97.1%) patients. After mean follow-up of 46.9 ± 15.7 months, 25 (73.5%) patients maintained sinus rhythm without AADs after a single procedure and 28 (82.4%) patients after repeated procedures.The recurrent ATs after RMV surgery and concomitant Cox-MAZE IV were mainly reentry mechanism, and largely related to LA. An incomplete lesion or re-conductive gaps in a prior lesion might be the predominant mechanisms for these ATs. Catheter-based mapping and ablation of these ATs seems to be effective and safe during a long-term follow-up.

9.
Lipids Health Dis ; 17(1): 252, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30400955

RESUMO

BACKGROUND: Although there have been many reports in the genetics of familial hypercholesterolemia (FH) worldwide, studies in regard of Chinese population are lacking. In this multi-center study, we aim to characterize the genetic spectrum of FH in Chinese population, and examine the genotype-phenotype correlations in detail. METHODS: A total of 285 unrelated index cases from China with clinical FH were consecutively recruited. Next-generation sequencing and bioinformatics tools were used for mutation detection of LDLR, APOB and PCSK9 genes and genetic analysis. RESULTS: Overall, the detection rate is 51.9% (148/285) in the unrelated index cases with a total of 119 risk variants identified including 84 in the LDLR gene, 31 in APOB and 4 in PCSK9 gene. Twenty-eight variants were found in more than one individual and LDLR c.1448G > A (p. W483X) was most frequent one detected in 9 patients. Besides, we found 8 (7 LDLR and 1 APOB) novel variants referred as "pathogenic (or likely pathogenic) variants" according to in silico analysis. In the phenotype analysis, patients with LDLR null mutation had significantly higher LDL cholesterol level than LDLR defective and APOB/PCSK9 mutation carriers and those with no mutations (p < 0.001). Furthermore, 13 double heterozygotes, 16 compound heterozygotes and 5 true LDLR homozygotes were identified and the true LDLR homozygotes had the most severe phenotypes. CONCLUSIONS: The present study confirmed the heterogeneity of FH genetics in the largest Chinese cohort, which could replenish the knowledge of mutation spectrum and contribute to early screening and disease management.

10.
Artigo em Inglês | MEDLINE | ID: mdl-30182188

RESUMO

Statins are widely used in the treatment of hypercholesterolemia. Studies have demonstrated that statins could maintain vascular contractile function through inhibiting the transformation of vascular smooth muscle cells (VSMCs) from the contractile phenotype to the synthetic phenotype. However, the underlying mechanisms have not been fully elucidated. The effect of atorvastatin on the thoracic aorta of Sprague-Dawley rats cultured in serum-free conditions in vitro was evaluated. Aortic constriction was induced by high potassium, phenylephrine, and CaCl2. The protein expression levels of α1 adrenoceptor; inositol 1,4,5-trisphosphate (IP3) receptor; protein kinase Cδ (PKCδ); stromal interaction molecule 1 (STIM1); high-voltage activated dihydropyridine-sensitive (L type, Cav1.2) channels; and two contractile phenotype marker proteins [α-smooth muscle actin (α-SMA) and myosin (SM-MHC)] were determined by western blotting. Compared with the fresh control, the constriction of rat aorta was impaired after culture in serum-free medium for 24 h. The impaired contraction of cultured aortas was mediated by Cav1.2 and store-operated Ca2+ (SOC) channel, which could be improved by atorvastatin at 20 µM. The protein expression levels of α1 adrenoceptor, IP3 receptor, PKCδ, STIM1, Cav1.2, α-SMA, and SM-MHC in the aortas cultured in serum-free conditions were decreased significantly. Atorvastatin partially prevented the reduction in the contractility and the downregulation of these proteins in cultured aortas. The transformation of the VSMC phenotype is associated with the vasoconstriction dysfunction of cultured aortas. Atorvastatin may protect vascular function by modulating calcium signaling pathways.

11.
J Geriatr Cardiol ; 15(6): 408-412, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30108612

RESUMO

Objective: To evaluate the predictive value of red cell distribution width (RDW) on left atrial thrombus (LAT) or left atrial spontaneous echo contrast (LASEC) in patients with non-valvular atrial fibrillation (AF). Methods: We reviewed 692 patients who were diagnosed as non-valvular AF and underwent transesophageal echocardiography (TEE) in Guangdong Cardiovascular Institute from April 2014 to December 2015. The baseline clinical characteristics, laboratory test of blood routine, electrocardiograph measurements were analyzed. Results: Eighty-four patients were examined with LAT/LASEC under TEE. The mean RDW level was significantly higher in LAT/LASEC patients compared with the non-LAT/LASEC patients (13.59% ± 1.07% vs. 14.34% ± 1.34%; P < 0.001). Receiver-operating characteristic curve analysis was performed and indicated the best RDW cut point was 13.16%. Furthermore, multivariate logistic regression analysis indicated that RDW level > 13.16% could be an independent risk factor for LAT/LASEC in patients with AF. Conclusion: Elevated RDW level is associated with the presence of LAT/LASEC and could be with moderate predictive value for LAT/LASEC in patients with non-valvular AF.

13.
Cardiology ; 140(2): 87-95, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29920487

RESUMO

OBJECTIVES: The aim of the study was to examine the association of CHADS2/CHA2DS2-VASc scores with left atrial thrombus (LAT) and spontaneous echocardiographic contrast (SEC) in non-anticoagulated nonvalvular atrial fibrillation (NVAF) spontaneous patients, and to develop a new scoring system for LAT/SEC prediction. METHODS: Consecutive non-anticoagulated NVAF patients with or without LAT/SEC by transesophageal echocardiography were identified in the Guangdong General Hospital. RESULTS: Among 2,173 patients, the prevalence of LAT/SEC was 4.9%. Both predictive values of CHADS2 and CHA2DS2-VASc scores for the presence of LAT/SEC were low-to-moderate (receiver operating characteristic [ROC] = 0.591 and 0.608, respectively, p = 0.90). By multivariate analysis, non-paroxysmal AF, decreased left ventricular ejection fraction, and left atrial enlargement were positively associated with LAT/SEC, while CHADS2/CHA2DS2VASc scores were not. A new scoring system based on these 3 factors above significantly improved the discrimination for LAT/SEC (ROC = 0.792). CONCLUSIONS: CHADS2/CHA2DS2-VASc scores had limited value in predicting LAT/SEC; a new scoring system that combines AF type and echocardiographic parameters may better predict LAT/SEC as a surrogate for cardioembolic risk in NVAF patients.

15.
Int J Cardiol ; 258: 103-108, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29467096

RESUMO

OBJECTIVES: To investigate the relationship between hyperuricemia and left atrial thrombus (LAT)/spontaneous echo contrast (SEC) and to determine the predictive value of hyperuricemia in non-valvular (NV) atrial fibrillation (AF) patients. METHODS: The study retrospectively reviewed 1198 consecutive patients (male 801, female 397, and mean age of 56.84 ±â€¯12.22) who were diagnosed with AF and accepted transesophageal echocardiography (TEE) prior to catheter ablation, appendage occlusion and electrical cardioversion using a single-center database. The clinical baseline characteristics were collected from medical record review and analyzed. Patients were categorized into an LAT/SEC group and a normal group. RESULTS: According to the TEE examination, there were 97 (8.1%) patients with abnormality; of these, 49 were with LAT and 48 with SEC. The mean serum uric acid (SUA) level and hyperuricemia proportion were markedly higher in patients with LAT/SEC. The significant predictive effect was observed in the SUA level (OR = 1.006) and hyperuricemia (OR = 2.04). After adjustment for persistent/permanent-AF, age, gender, LA dimension > 40 mm, previous stroke, hypertension and diabetes, the SUA level (OR = 1.004) and hyperuricemia (OR = 1.69) were independent predictors for LAT/SEC. The SUA level (OR = 1.004) and hyperuricemia (OR = 1.69) were independent predictors for LAT/SEC, Further subgroup analysis in different CHA2DS2-VASc categories, it might be helpful to refine the LAT/SEC risk via combination area CHA2DS2-VASc score and hyperuricemia, especially in those with CHA2DS2-VASc score < 2. CONCLUSIONS: The SUA level and hyperuricemia proportion are closely associated with LA stasis. Hyperuricemia might independently predict and refine LA stasis risk among NVAF patients, especially in those with CHA2DS2-VASc score < 2.


Assuntos
Fibrilação Atrial/sangue , Fibrilação Atrial/diagnóstico por imagem , Átrios do Coração/diagnóstico por imagem , Hiperuricemia/sangue , Hiperuricemia/diagnóstico por imagem , Adulto , Idoso , Fibrilação Atrial/epidemiologia , Ecocardiografia/tendências , Feminino , Humanos , Hiperuricemia/epidemiologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Ácido Úrico/sangue
16.
Cell Death Dis ; 9(3): 301, 2018 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-29467540

RESUMO

Our recent study identified a list of differentially expressed microRNAs (miRNAs) in human prostate cancer (PCa) tissues compared to adjacent benign prostate tissues. In the current study, to identify the crucial miRNA-mRNA regulatory biomodule involved into prostate carcinogenesis based on the previous miRNA expression profile in PCa, we proposed an integrated systematic approach which combined miRNA-mediated gene expression regulatory network analysis, experimental validations in vitro and in vivo, as well as clinical significance evaluation. As a result, the CCND1-RNASEL-CDKN1A-TP73-MDM2-UBE2I axis was identified as a bottleneck in the miRNA-mediated gene expression regulatory network of PCa according to network topological analysis. The direct binding relationship between TP73 and PCa downregulated miR-193a-5p, and the direct binding relationship between UBE2I and PCa upregulated miR-188-5p were both experimentally validated. In addition, miR-193a-5p had a more significant regulatory effect on the tumor promoter isoform of TP73-deltaNp73 than on the tumor suppressive isoform of TP73-TAp73. Importantly, the deregulation of either the miR-193a-5p-TP73 or miR-188-5p-UBE2I axes was significantly associated with aggressive progression and poor prognosis in PCa patients. Gain- and loss-of-function experiments showed that miR-193a-5p efficiently inhibited in vitro PCa cell proliferation, migration, and invasion, and in vivo tumor growth, and markedly induced PCa cell apoptosis via regulating TP73 with a corresponding suppression of the CCND1-RNASEL-CDKN1A-MDM2 axis. In contrast, miR-188-5p exerted its tumor promoter roles through targeting UBE2I with a subsequent activation of the CCND1-RNASEL-CDKN1A-MDM2 axis. Taken together, this integrated analysis revealed the potential roles of the miR-193a-5p/TP73 and miR-188-5p/UBE2i negative regulation pairs in PCa. In addition to the significant clinical relevance, miR-193a-5p- and miR-188-5p-regulated CCND1-RNASEL-CDKN1A-TP73-MDM2-UBE2I signaling may be a novel regulatory biomodule in prostate carcinogenesis.

17.
Mol Med Rep ; 17(2): 3425-3431, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29257298

RESUMO

Atrial fibrosis is the fundamental characteristic of the structural pathology associated with atrial fibrillation (AF). Inflammation can contribute to atrial fibrosis, engendering AF. The present study aimed to investigate the role of macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, in the regulation of proliferation and function of cardiac fibroblasts (CFs). Biochemical assays were performed to examine the expression of extracellular matrix (ECM) in human atrial tissues, and the proliferation and regulation of ECM induced by MIF in CFs. The expression of ECM, including collage type 3, α1 (Col­3A1), matrix metalloproteinase (MMP)­2/-9 and transforming growth factor (TGF)­ß was higher in patients with permanent AF, compared with patients in sinus rhythm (SR), and the expression levels of MIF were also increased in AF. Treatment of CFs with mouse recombinant MIF (rMIF; 40 nM) for 48 h was found to promote the proliferation of CFs. The MIF­induced CF proliferation was completely inhibited by tyrosine kinase inhibitor­PP1. rMIF treatment also stimulated the activation of Src kinase in CFs. In addition, MIF treatment upregulated the expression levels of fibrosis­related proteins, Col­1, Col­3, MMP­2/-9 and TGF­ß, in the CFs. These results suggested that MIF was involved in the structural remodeling that accompanies AF, possibly by promoting the proliferation of CFs and increasing the expression of ECM. These data implicate inflammation as a potential driver of CF.


Assuntos
Arritmia Sinusal/patologia , Fibrilação Atrial/patologia , Proliferação de Células , Fibroblastos/patologia , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Transdução de Sinais , Quinases da Família src/metabolismo , Adulto , Animais , Arritmia Sinusal/metabolismo , Fibrilação Atrial/metabolismo , Colágeno/análise , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Feminino , Fibroblastos/metabolismo , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Humanos , Oxirredutases Intramoleculares/análise , Fatores Inibidores da Migração de Macrófagos/análise , Masculino , Metaloproteinase 2 da Matriz/análise , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/análise , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Pessoa de Meia-Idade
18.
Sci Rep ; 7(1): 11879, 2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-28928469

RESUMO

The molecular mechanisms underlying anthracyclines-induced cardiotoxicity have not been well elucidated. MiRNAs were revealed dysregulated in the myocardium and plasma of rats received Dox treatment. MicroRNA-34a-5p (miR-34a-5p) was verified increased in the myocardium and plasma of Dox-treated rats, but was reversed in rats received Dox plus DEX treatments. Human miR-34a-5p was also observed increased in the plasma of patients with diffuse large B-cell lymphoma after 9- and 16-week epirubicin therapy. Up-regulation of miR-34a-5p was observed in Dox-induced rat cardiomyocyte H9c2 cells. MiR-34a-5p could augment Bax expression, but inhibited Bcl-2 expression, along with the increases of the activated caspase-3 and mitochondrial potentials in H9C2 cells. MiR-34a-5p was verified to modulate Sirt1 expression post-transcriptionally. In parallel to Sirt1 siRNA, miR-34a-5p could enhance p66shc expression, accompanied by increases of Bax and the activated caspase-3 and a decrease of Bcl-2 in H9c2 cells. Moreover, enforced expression of Sirt1 alleviated Dox-induced apoptosis of H9c2 cells, with suppressing levels of p66shc, Bax, the activated caspase-3 and miR-34a-5p, and enhancing Bcl-2 expression. Therefore, miR-34a-5p enhances cardiomyocyte apoptosis by targeting Sirt1, activation of miR-34a-5p/Sirt1/p66shc pathway contributes to Dox-induced cardiotoxicity, and blockage of this pathway represents a potential cardioprotective effect against anthracyclines.

19.
Clin Exp Pharmacol Physiol ; 44(7): 771-778, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28429502

RESUMO

Connexin 43 (Cx43) plays an important role in the pathogenesis of atrial fibrillation (AF). The present study sought to investigate the effect of macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, on Cx43 expression and activity and determine the intracellular signalling pathways. Cx43 protein and mRNA levels were assayed using immunofluorescence, real-time polymerase chain reaction (PCR), and western blot. We found that increased MIF and extracellular regulated protein kinases (ERK) expression was accompanied by a significant reduction in Cx43 protein expression in atrial tissues from patients with AF compared with those with sinus rhythm. In cultured atrium-derived myocytes (HL-1 cells), mouse recombinant-MIF (rMIF, 20 or 40 nmol/L, 24 hours) down-regulated gene and protein expression of Cx43 in a concentration-dependent manner. U0126, a specific inhibitor of mitogen-activated protein kinase kinase (MAPKK) could reverse the decrease in expression of Cx43 protein induced by rMIF. Further studies revealed that rMIF (40 nmol/L, 15, 30, and 45 minutes) was able to stimulate phospho-Erk1/2 (Thr202/Tyr204) production in a time-dependent manner. These results suggest that MIF is involved in the pathogenesis of AF, probably by down-regulating the protein and gene expression of Cx43 via ERK1/2 kinase activation. Our findings represent a potential pathogenic mechanism in AF.


Assuntos
Conexina 43/metabolismo , Átrios do Coração/citologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miócitos Cardíacos/metabolismo , Adulto , Animais , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Conexina 43/genética , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Átrios do Coração/patologia , Humanos , Fatores Inibidores da Migração de Macrófagos/farmacologia , Masculino , Camundongos , Pessoa de Meia-Idade , Miócitos Cardíacos/citologia , Miócitos Cardíacos/patologia , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Nó Sinoatrial/efeitos dos fármacos , Nó Sinoatrial/fisiologia , Nó Sinoatrial/fisiopatologia
20.
Eur J Pharmacol ; 805: 93-100, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28286123

RESUMO

Thromboxane A2 (TXA2) has been implicated in the pathogenesis of diabetic vascular complications, although the underlying mechanism remains unclear. The present study investigated the alterations in TXA2 receptor signal transduction in type 2 diabetic renal arteries. The contraction of renal arterial rings in control (db/m+) mice and type 2 diabetic (db/db) mice was measured by a Multi Myograph System. Intracellular calcium concentration ([Ca2+]i) in vascular smooth muscle cells was measured by Fluo-4/AM dye and confocal laser scanning microscopy. Quantitative real-time PCR and Western blot analysis were used to determine gene and protein expression levels, respectively. A stable TXA2 mimic U46619 caused markedly stronger dose-dependent contractions in the renal arteries of db/db mice than in those of db/m+ mice. This response was completely blocked by a TXA2 receptor antagonist GR32191 and significantly inhibited by U73122. U46619-induced vasoconstriction was increased in the presence of nifedipine in db/db mice compared with that in db/m+ mice, whereas the response to U46619 did not differ between the two groups in the presence of SKF96365. Sarcoplasmic reticulum Ca2+ release-mediated and CaCl2-induced contractions did not differ between the two groups. In db/db mice, store-operated Ca2+(SOC) entry-mediated contraction in the renal arteries and SOC entry-mediated Ca2+ influx in smooth muscle cells were significantly increased. And the gene and protein expressions of TXA2 receptors, Orai1 and Stim1 were upregulated in the diabetic renal arteries. Therefore the enhancement of U46619-induced contraction was mediated by the upregulation of TXA2 receptors and downstream signaling in the diabetic renal arteries.


Assuntos
Artérias/fisiopatologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Rim/irrigação sanguínea , Receptores de Tromboxano A2 e Prostaglandina H2/metabolismo , Vasoconstrição , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Animais , Artérias/efeitos dos fármacos , Canais de Cálcio/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos
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