Coagulation balance is maintained through fine-tuned interactions among clotting factors, whose physiological concentrations vary substantially. In particular, the concentrations of coagulation proteases (pM to nM) are much lower than their natural inactivator antithrombin (AT,~3 μM), suggesting the existence of other coordinators. In the current study, we found that transferrin (normal plasma concentration~40 μM) interacts with fibrinogen, thrombin, factor XIIa (FXIIa), and AT with different affinity to maintain coagulation balance. Normally, transferrin is sequestered by binding with fibrinogen (normal plasma concentration~10 μM) at a molar ratio of 4:1. In atherosclerosis, abnormally up-regulated transferrin interacts with and potentiates thrombin/FXIIa and blocks AT's inactivation effect on coagulation proteases by binding to AT, thus inducing hypercoagulability. In the mouse model, transferrin overexpression aggravated atherosclerosis, whereas transferrin inhibition via shRNA knockdown or treatment with antitransferrin antibody or designed peptides interfering with transferrin-thrombin/FXIIa interactions alleviated atherosclerosis. Collectively, these findings identify that transferrin is an important clotting regulator and an adjuster in the maintenance of coagulation balance and modifies the coagulation cascade.

BackgroundMetastasis associated lung adenocarcinoma transcript 1 (MALAT1) plays an important role in vascular remodeling. Down-regulation of MALAT1 can inhibit the proliferation of vascular endothelial cells and vascular smooth muscle cells, reduce cardiomyocyte apoptosis and improve left ventricular function, which is closely linked to numerous pathological processes such as coronary atherosclerotic heart disease (CAD). The aim of this study was to investigate whether polymorphisms in MALAT1 were associated with the susceptibility to CAD.MethodsA total of 508 CAD patients and 562 age-, gender-, and ethnicity-matched controls were enrolled in this study. Four polymorphisms in MALAT1 (i.e., rs11227209, rs619586, rs664589, and rs3200401) were genotyped using a TaqMan allelic discrimination assay.ResultsThe rs619586 AG/GG genotypes and G allele were associated with a reduced risk of CAD (AG/GG vs. AA: adjusted OR = 0.66, 95% CI: 0.48–0.91; G vs. A: adjusted OR = 0.68, 95% CI: 0.51–0.90). Stratification analyses showed that CAD patients with rs11227209 CG/GG, rs619586 AG/GG, and rs3200401 CT/TT genotypes exhibited lower levels of TCH (P = 0.02, 0.04, and 0.02, respectively). Moreover, CGCC haplotype was associated with a decreased risk of CAD (OR = 0.28, 95% CI: 0.16–0.48). Multivariate logistic regression analysis identified some independent risk factors for CAD, including rs619586 and rs664589. Subsequent combined analysis showed that the combined genotypes of rs619586AG/GG and rs664589CC were associated with a reduced risk of CAD (OR = 0.29; 95%CI, 0.16–0.53).ConclusionsThese findings indicate that rs619586AG/GG genotypes in MALAT1 may protect against the occurrence of CAD.Electronic supplementary materialThe online version of this article (10.1186/s12944-018-0728-2) contains supplementary material, which is available to authorized users.

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Although detergent-based decellularization protocols have been widely used to obtain a natural extracellular matrix (ECM) scaffold in tissue engineering, some key challenges still exist. To achieve an optimum natural decellularized scaffold for the construction of tissue-engineered small-diameter blood vessels (TEBV), porcine carotid arteries (PCAs) were decellularized by combining sodium dodecyl sulfate (SDS), sodium deoxycholate (SDC) and Triton X-100 (Triton) in different concentrations. Tissue samples were processed and their histological, biochemical and biomechanical characteristics were investigated. Results showed that only two methods 0.5% (SDS + SDC) and 1% (SDS + SDC) could completely remove of the cellular contents and preserve the native ECM architecture. Furthermore, 1% (SDS + SDC) based methods acquire preferable porosity and suitable mechanical strength. Residual Triton in the ECM scaffold holds intensive cytotoxity. In conclusion, 1%(SDS + SDC) based method can obtain a superior PCAs scaffold for the construction of TEBV. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 619-631, 2018.

Studies have shown significantly increased thromboembolic events at high-altitude. We recently reported that transferrin could potentiate blood coagulation, but the underlying mechanism for high-altitude-related thromboembolism is still poorly understood. Here, we examined the activity and concentration of plasma coagulation factors and transferrin in plasma collected from long-term human residents and short-stay mice exposed to varying altitudes. We found that the activities of thrombin and FXIIa along with the concentrations of transferrin were significantly increased in the plasma of humans and mice at high altitudes. Furthermore, both hypoxia (6% O2) and low temperature (0 °C), two critical high-altitude factors, enhanced hypoxia-inducible factor (HIF)-1a levels to promote the expression of the transferrin gene, whose enhancer region contains HIF-1a binding site, and consequently to induce hypercoagulability by potentiating thrombin and FXIIa. Importantly, thromboembolic disorders and pathological insults in mouse models induced by both hypoxia and low temperature were ameliorated by transferrin interferences, including transferrin antibody treatment, transferrin down-regulation, and the administration of our designed peptides that inhibit the potentiation of transferrin on thrombin and FXIIa. Thus, low temperature and hypoxia up-regulated transferrin expression promoted hypercoagulability. Our data suggest that targeting the transferrin-coagulation pathway is a novel and may be a powerful strategy against thromboembolic events caused by harmful environmental factors under high-altitude conditions.

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BackgroundInconsistent results were reported in recent literature regarding the association between methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and the susceptibility of congenital heart disease (CHD). In this study, we performed a meta-analysis to investigate the associations by employing multiple analytical methods.MethodsLiterature search was performed and published articles were obtained from PubMed, Embase and CNKI databases based on the exclusion and inclusion criteria. Data were extracted from eligible studies and the crude odds ratios and their corresponding 95% confidence intervals (CIs) were calculated using random or fix effects model to evaluate the associations between the MTHFR C677T/A1298C polymorphisms and CHD development. Subgroup based analysis was performed by Hardy–Weinberg equilibrium, ethnicity, types of CHD, source of control and sample size.ResultsTwenty-four eligible studies were included in this meta-analysis. Significant association was found between fetal MTHFR C677T polymorphism and CHD development in all genetic models. The pooled ORs and 95% CIs in all genetic models indicated that MTHFR C677T polymorphism was significantly associated with CHD in Asian, but not Caucasian in subgroup analysis. The maternal MTHFR C677T polymorphism was not associated with CHD except for recessive model. Moreover, neither maternal nor fetal MTHFR A1298C polymorphism was associated with CHD.ConclusionThe fetal MTHFR C677T polymorphism may increase the susceptibility to CHD. Fetal MTHFR C677T polymorphism was more likely to affect Asian fetus than Caucasian. The MTHFR A1298C polymorphism may not be a risk of congenital heart disease.