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BACKGROUND AND PURPOSE: Reducing hypertensive myocardial fibrosis is the fundamental approach to preventing hypertensive ventricular remodelling. C1q/TNF-related protein-3 (CTRP3) is closely associated with hypertension. However, the role and mechanism of CTRP3 in hypertensive myocardial fibrosis are unclear. In this study, we aimed to explore the effect of CTRP3 on hypertensive myocardial fibrosis and the potential mechanism. METHODS AND RESULTS: WKY and SHR rats were employed, blood pressure, body weight, heart weight, H/BW were measured, and fibrotic-related proteins, CTRP3 and Collagen I were tested in myocardium at 12 and 20âweeks by immunohistochemical staining and Western blotting, respectively. The results showed that compared with the WKY, SBP, DBP, mean arterial pressure and heart rate (HR) were all significantly increased in SHR at 12 and 20âweeks, while heart weight and H/BW were only increased at 20âweeks. Meanwhile, CTRP3 decreased, while Collagen I increased significantly in the SHR rat myocardium at 20âweeks, which compared to the WKY. Moreover, the expression of α-SMA increased from 12âweeks, Collagen I/III and MMP2/9 increased and TIMP-2 decreased until 20âweeks. In order to explore the function and mechanism of CTRP3 in hypertensive fibrosis, Angiotensin II (Ang II) was used to induce hypertension in primary neonatal rat cardiac fibroblasts in vitro . CTRP3 significantly inhibited the Ang II induced activation of fibrotic proteins, purinergic 2X7 receptor (P2X7R)-NLRP3 inflammasome pathway. The P2X7R agonist BzATP significantly exacerbated Ang II-induced NLRP3 inflammasome activation, which was decreased by the P2X7R antagonists A43079, CTRP3 and MCC950. CONCLUSION: CTRP3 expression was decreased in the myocardium of SHR rats, and exogenous CTRP3 inhibited Ang II-induced fibrosis in cardiac fibroblasts by regulating the P2X7R-NLRP3 inflammasome pathway, suggesting that CTRP3 is a potential drug for alleviating myocardial fibrosis in hypertensive conditions.
Assuntos
Cardiomiopatias , Hipertensão , Ratos , Animais , Ratos Endogâmicos SHR , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Complemento C1q/metabolismo , Ratos Endogâmicos WKY , Cardiomiopatias/complicações , Miocárdio/patologia , Hipertensão/complicações , Angiotensina II/farmacologia , Colágeno/metabolismo , FibroseRESUMO
Acute myocardial infarction (AMI) continues as the main cause of morbidity and mortality worldwide. Interestingly, emerging evidence highlights the role of gut microbiota in regulating the pathogenesis of coronary heart disease, but few studies have systematically assessed the alterations and influence of gut microbiota in AMI patients. As one approach to address this deficiency, in this study the composition of fecal microflora was determined from Chinese AMI patients and links between gut microflora and clinical features and functional pathways of AMI were assessed. Fecal samples from 30 AMI patients and 30 healthy controls were collected to identify the gut microbiota composition and the alterations using bacterial 16S rRNA gene sequencing. We found that gut microflora in AMI patients contained a lower abundance of the phylum Firmicutes and a slightly higher abundance of the phylum Bacteroidetes compared to the healthy controls. Chao1 (P = 0.0472) and PD-whole-tree (P = 0.0426) indices were significantly lower in the AMI versus control group. The AMI group was characterized by higher levels of the genera Megasphaera, Butyricimonas, Acidaminococcus, and Desulfovibrio, and lower levels of Tyzzerella 3, Dialister, [Eubacterium] ventriosum group, Pseudobutyrivibrio, and Lachnospiraceae ND3007 group as compared to that in the healthy controls (P < 0.05). The common metabolites of these genera are mostly short-chain fatty acids, which reveals that the gut flora is most likely to affect the occurrence and development of AMI through the short-chain fatty acid pathway. In addition, our results provide the first evidence revealing remarkable differences in fecal microflora among subgroups of AMI patients, including the STEMI vs. NSTEMI, IRA-LAD vs. IRA-Non-LAD and Multiple (≥2 coronary stenosis) vs. Single coronary stenosis groups. Several gut microflora were also correlated with clinically significant characteristics of AMI patients, including LVEDD, LVEF, serum TnI and NT-proBNP, Syntax score, counts of leukocytes, neutrophils and monocytes, and fasting serum glucose levels. Taken together, the data generated enables the prediction of several functional pathways as based on the fecal microfloral composition of AMI patients. Such information may enhance our comprehension of AMI pathogenesis.
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BACKGROUND: The present study analyzed the synergistic protective effect of ß-alanine and taurine against myocardial ischemia/reperfusion. Myocardial infarct size, lipid peroxidation, and levels of glutathione peroxidase (Gpx), superoxide dismutase (SOD), reduced glutathione (GSH), catalase, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), reactive oxygen species (ROS), apoptosis, and the mRNA and protein expression of Janus kinase 2 (JAK2) and signal transducer and activator 3 of transcription (STAT3) were determined. The molecular docking was carried out by using AutoDock 4.2.1. RESULTS: Combined treatment with ß-alanine and taurine reduced myocardial infarct size, lipid peroxidation, inflammatory marker, ROS levels, and apoptosis and increased Gpx, SOD activity, GSH, and catalase activity. Furthermore, combined treatment significantly reduced JAK2 and STAT3 mRNA and protein expression compared with the control. The small molecule was docked over the SH2 domain of a STAT3, and binding mode was determined to investigate the inhibitory potential of ß-alanine and taurine. ß-Alanine bound to SH2 domain with ΔG of -7.34â¯kcal/mol and KI of 1.91⯵M. Taurine bound to SH2 domain with ΔG of -7.38â¯kcal/mol and KI of 1.95⯵M. CONCLUSION: Taken together, these results suggest that the combined supplementation of ß-alanine and taurine should be further investigated as an effective therapeutic approach in achieving cardioprotection in myocardial ischemia/reperfusion.
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Animais , Masculino , Ratos , Taurina/uso terapêutico , Cardiotônicos/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , beta-Alanina/uso terapêutico , Isquemia Miocárdica/tratamento farmacológico , Superóxido Dismutase , Imuno-Histoquímica , Peroxidação de Lipídeos , Espécies Reativas de Oxigênio , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Modelos Animais de Doenças , Janus Quinase 2 , Simulação de Acoplamento Molecular , Glutationa Peroxidase , Cardiopatias/tratamento farmacológico , InflamaçãoRESUMO
Testosterone deficiency is present in a certain proportion men with chronic heart failure (CHF). Low testosterone levels in American and European patients with CHF lead to the high mortality and readmission rates. Interestingly, this relationship has not been studied in Chinese patients. To this end, 167 Chinese men with CHF underwent clinical and laboratory evaluations associated with determinations of testosterone levels. Total testosterone (TT) levels and sex hormone-binding globulin were measured by chemiluminescence or immunoassays assays and free testosterone (FT) levels were calculated, Based upon results from these assays, patients were divided into either a low testosterone (LT; n = 93) or normal testosterone (NT; n = 74) group. Subsequently, records from each patient were reviewed over a follow-up duration of at least 3 years. Patients in the LT group experienced worse cardiac function and a higher prevalence of etiology (ischemic vs. no ischemic) and comorbidity (both P < 0.05). In addition, readmission rates of patients in the LT group were higher than that of patients in the NT group (3.32 ± 1.66 VS 1.57 ± 0.89). Overall, deficiencies in FT levels were accompanied with increased mortalities (HR = 6.301, 95% CI 3.187-12.459, P < .0001).
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OBJECTIVE: To determine the rate of low health literacy in the rheumatoid arthritis (RA) population in southwestern Ontario. METHODS: For the study, 432 patients with RA were contacted, and 311 completed the assessment. The health literacy levels of the participants were estimated using 4 assessment tools administered in the following order: the Single Item Literacy Screener (SILS), the Medical Term Recognition Test (METER), the Rapid Estimate of Adult Literacy in Medicine (REALM), and the Shortened Test of Functional Health Literacy in Adults (STOFHLA). RESULTS: The rates of low literacy as estimated by STOFHLA, REALM, METER, and SILS were 14.5%, 14.8%, 14.1%, and 18.6%, respectively. All 4 assessment tools were statistically significantly correlated. STOFHLA, REALM, and METER were strongly correlated with each other (r = 0.59-0.79), while SILS only demonstrated moderate correlations with the other assessment tools (r = 0.33-0.45). Multiple linear regression and binary logistic regression analyses revealed that low levels of education and a lack of daily reading activity were common predictors of low health literacy. Using a non-English primary language at home was found to be a strong predictor of low health literacy in STOFHLA, REALM, and METER. Male sex was found to be a significant predictor of poor performance in REALM and METER, but not STOFHLA. CONCLUSION: Low health literacy is an important issue in the southwestern Ontario RA population. About 1 in 7 patients with RA may not have the necessary skills to become involved in making decisions regarding their personal health. Rheumatologists should be aware of the low health literacy levels of patients with RA and should consider identifying patients at risk of low health literacy.
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Artrite Reumatoide , Conhecimentos, Atitudes e Prática em Saúde , Letramento em Saúde , Fatores Etários , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Ontário , Relações Médico-Paciente , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
Tumor necrosis factor-α, platelet-derived growth factor, matrix metalloproteinases 9 and 2 have very important roles in neointimal hyperplasia, which develops after endovascular injury. However, the relationships among the four factors in inducing neointimal hyperplasia are unclear. Here, we used a mouse model of femoral arterial transluminal wire injury, and examined neointimal hyperplasia within the 28 days that followed the injury. We confirmed that the neointima kept growing during the 28 days, and found that expression of TNF-α and PDGF mRNAs in femoral arteries peaked within 24h after injury. However, MMP9 mRNA expression peaked 7 days, and MMP2 mRNA expression peaked 28 days after injury. Then, we administered exogenous TNF-α or PDGF to the peri-femoral artery following an injury, and found that exogenous TNF-α led to significantly more neointimal hyperplasia during the first 2 weeks, and PDGF led to increased neointimal hyperplasia during the second 2 weeks after injury. We also used the model of femoral artery injury in MMP9- or MMP2-deficient (MMP9-/- or MMP2-/-) mice. We found that neointimal hyperplasia was reduced in MMP9-/- mice during the first 2 weeks after injury, and neointimal hyperplasia was reduced in MMP2-/- mice during the second 2 weeks after injury. When TNF-α or PDGF was administered to the peri-femoral artery immediately after injury, TNF-α did not promote neointimal hyperplasia in MMP9-/- mice during the first 2 weeks after injury but did in MMP2-/- mice, and PDGF did not promote neointimal hyperplasia in MMP2-/- mice during the second 2 weeks after injury but did in MMP9-/- mice. We used an in vitro system to treat vascular smooth muscle cells (VSMCs) with TNF-α or PDGF; TNF-α induced MMP9, but not MMP2, expression at a fast reaction speed, while PDGF induced MMP2, but not MMP9, expression at a slow reaction speed. Meanwhile, TNF-α induced VSMC migration in a MMP9-dependent manner, and PDGF induced VSMC proliferation in a MMP2-dependent manner. Taken together, our studies elucidated the axis of TNF-α-MMP9-VSMC migration and PDGF-MMP2-VSMC proliferation, both of which contributed to the mechanism of neointimal hyperplasia formation.