Experimental and clinical observations suggest that E-selectin could have an important role in essential hypertension (EH), but the relationship between common E-selectin variants and EH has not been extensively studied in the Chinese population. In this study, we explored the association between two common variants in the E-selectin gene (rs5361A/C and rs5355C/T) and EH in the Uygur, Kazakh and Han populations in the Xinjiang area. A case-control study was conducted to explore the association between these two single-nucleotide polymorphisms and EH in a large sample size, including 941 EH subjects (309 Uygur, 264 Kazakh and 368 Han individuals) and 924 control subjects (300 Uygur, 275 Kazakh and 349 Han individuals). Univariate analysis showed that the rs5361 A/C polymorphism was significantly associated with EH in the Uygur (P¼0.002) and Han (P¼3.6Â10 À7 ) populations. The CC genotype of this SNP was present only in patients with EH in all of the three nationalities studied. Han individuals who carry the CC genotype of rs5361 were more susceptible to EH, according to the dominant models (P¼1.13Â10 À4 , odds ratio¼3.812, 95% confidence interval: 1.685-7.792), but there was no association of genotype with EH for the other ethnicities. No significant difference in rs5355 C/T polymorphism rate was found between the EH and control groups. Our results indicate that the common variant rs5361 is strongly associated with EH in Han individuals and weakly associated in Uygur individuals. The CC genotype of rs5361 might be an independent risk factor for EH among Uygur, Kazakh and Han individuals in the Xinjiang area.
Background:
Pathological cardiac hypertrophy is one of the leading causes of heart failure with highly complicated pathogeneses. The E3 ligase TRIM16 (tripartite motif–containing protein 16) has been recognized as a pivotal regulator to control cell survival, immune response, and oxidative stress. However, the role of Trim16 in cardiac hypertrophy is unknown.
Methods:
We generated cardiac-specific knockout mice and adeno-associated virus serotype 9–Trim16 mice to evaluate the function of Trim16 in pathological myocardial hypertrophy. The direct effect of TRIM16 on cardiomyocyte enlargement was examined using an adenovirus system. Furthermore, we combined RNA-sequencing and interactome analysis that was followed by multiple molecular biological methodologies to identify the direct target and corresponding molecular events contributing to TRIM16 function.
Results:
We found an intimate correlation of Trim16 expression with hypertrophy-related heart failure in both human and mouse. Our functional investigations and unbiased transcriptomic analyses clearly demonstrated that Trim16 deficiency markedly exacerbated cardiomyocyte enlargement in vitro and in transverse aortic constriction–induced cardiac hypertrophy mouse model, whereas Trim16 overexpression attenuated cardiac hypertrophy and remodeling. Mechanistically, Prdx1 (peroxiredoxin 1) is an essential target of Trim16 in cardiac hypertrophy. We found that Trim16 interacts with Prdx1 and inhibits its phosphorylation, leading to a robust enhancement of its downstream Nrf2 (nuclear factor–erythroid 2–related factor 2) pathway to block cardiac hypertrophy. Trim16-blocked Prdx1 phosphorylation was largely dependent on a direct interaction between Trim16 and Src and the resultant Src ubiquitinational degradation. Notably, Prdx1 knockdown largely abolished the anti-hypertrophic effects of Trim16 overexpression.
Conclusions:
Our findings provide the first evidence supporting Trim16 as a novel suppressor of pathological cardiac hypertrophy and indicate that targeting the Trim16-Prdx1 axis represents a promising therapeutic strategy for hypertrophy-related heart failure.
Ischemia-reperfusion (I/R) injury causes cardiac dysfunction through several mechanisms including the irregular expression of some long noncoding RNA. However, the role of SNHG12 in myocardial I/R injury remains unclear. Here, we found the increase of the SNHG12 level in hypoxia-reoxygenation (H/R)-injured-H9c2 cells. SNHG12 silencing enhanced the apoptosis of H/R-injured H9c2 cells, while SNHG12 overexpression relieved the cardiomyocyte apoptosis induced by H/R stimulation. Additionally, the suppression of SNHG12 significantly boosted the H/R-induced expression and the production of TNF-α, IL-6, and IL-1β, as well as the activation of NF-κB, which were fully reversed after overexpression of SNHG12. Mechanistically, SNHG12 adversely regulated the production of receptor for advanced glycation end products (RAGE) in H/R-stimulated H9c2 cells. Antibody blocking of RAGE alleviated the apoptosis of H/R-injured H9c2 cells. Collectively, we have determined a valuable mechanism by which the high level of SNHG12 contributes to H9c2 cells against H/R injury through the reduction of RAGE expression.
Our results indicated that the C-allele of rs3087894 in DDAH1 was a risk factor for hypertension in the Kazakh group but a protective factor in the Uygur group.
Objective: Ischemic cardiomyopathy (ICM) is a major cardiovascular state associated with prominently increased morbidity and mortality. Our purpose was to detect reliable gene signatures for ICM through integrated feature selection strategies.Methods: Transcriptome profiles of ICM were curated from the GEO project. Classification models, including least absolute shrinkage and selection operator (LASSO), support vector machine (SVM), and random forest, were adopted for identifying candidate ICM-specific genes for ICM. Immune cell infiltrates were estimated using the CIBERSORT method. Expressions of candidate genes were verified in ICM and healthy myocardial tissues via Western blotting. JC-1 staining, flow cytometry, and TUNEL staining were presented in hypoxia/reoxygenation (H/R)-stimulated H9C2 cells with TRMT5 deficiency.Results: Following the integration of three feature selection methods, we identified seven candidate ICM-specific genes including ASPN, TRMT5, LUM, FCN3, CNN1, PCNT, and HOPX. ROC curves confirmed the excellent diagnostic efficacy of this combination of previous candidate genes in ICM. Most of them presented prominent interactions with immune cell infiltrates. Their deregulations were confirmed in ICM than healthy myocardial tissues. TRMT5 expressions were remarkedly upregulated in H/R-stimulated H9C2 cells. TRMT5 deficiency enhanced mitochondrial membrane potential and reduced apoptosis in H/R-exposed H9C2 cells.Conclusion: Collectively, our findings identified reliable gene signatures through combination strategies of diverse feature selection methods, which facilitated the early detection of ICM and revealed the underlying mechanisms.
Jointly extracting entities and classifying relations aims to detect all possible triples from unstructured text with a single model. Tagging-based method effectively improves the performance of jointly relation extraction. However, some taggingbased approaches ignored that one entity pair may exist multiple relations and others set an empirical threshold value for selecting one or more relevant relations, which becomes the bottlenecks of the model. As a solution, we propose the attention guided filter, namely, AGFRel, which introduces transformer blocks to learn the number of relations for every entity pair to filter out irrelevant relations. Moreover, each module of the model has a multi-head attention guided layer to highlight valuable information. Extensive experimental results show that AGFRel is capable of gaining better performance on various tasks including overlapping triples extraction and multiple triples extraction. On NYT and WebNLG public datasets, our model obtains F1 score 90.8 and 91.9 respectively and achieves a new state-of-the-art performance.
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