Dataset Information

Differential Expression of TXNIP Isoforms in the Peripheral Leukocytes of Patients with Acute Myocardial Infarction.

ABSTRACT: Background:Acute myocardial infarction (AMI) is the most serious type of coronary atherosclerotic heart disease (CAD). The pathological changes are characterized by atherosclerosis. Oxidative stress plays an important role in atherosclerosis. Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor and regulator of thioredoxin, could bind thioredoxin to regulate its expression and antioxidant activity negatively. The NCBI data show that there are two isoforms in TXNIP gene, namely, TXNIP1 and TXNIP2. Our previous studies have shown that TXNIP expression levels in patients with unstable angina pectoris (UAP) were increased compared with controls (CTR). However, no upregulation of TXNIP was detected in AMI patients. Methods:The leucocytes were isolated from peripheral venous blood, and total RNA of the leucocytes was extracted. Then, real-time quantitative PCR was performed. Results:mRNA levels of TXNIP2 in AMI were significantly increased compared with CTR (P < 0.05). However, the expression of TXNIP1 was downregulated in AMI, but the difference was not statistically significant (P > 0.05). Logistic regression analysis showed that TXNIP2 mRNA levels were significantly associated with AMI (OR?=?2.207, P < 0.05). Conclusions:The expression of TXNIP2, not TXNIP1, is upregulated in leukocytes of AMI patients, indicating that only TXNIP2 in circulating leucocytes may be involved in the pathogenesis of AMI.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6032985 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Differential Expression of TXNIP Isoforms in the Peripheral Leukocytes of Patients with Acute Myocardial Infarction.

Zhang Yujing Y Zhong Peng P Xu Yingze Y Wang Baokui B Zhu Tao T Zhang Wendi W Wang Haihua H Wei Zixiu Z Huang Jian J

Disease markers 20180621

<h4>Background</h4>Acute myocardial infarction (AMI) is the most serious type of coronary atherosclerotic heart disease (CAD). The pathological changes are characterized by atherosclerosis. Oxidative stress plays an important role in atherosclerosis. Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor and regulator of thioredoxin, could bind thioredoxin to regulate its expression and antioxidant activity negatively. The NCBI data show that there are two isoforms in TXNIP gene, namel ...[more]

PMID: 30034557

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Project description:RationaleThioredoxin-interacting protein (Txnip) is a novel molecular target with translational potential in diverse human diseases. Txnip has several established cellular actions including binding to thioredoxin, a scavenger of reactive oxygen species (ROS). It has been long recognized from in vitro evidence that Txnip forms a disulfide bridge through cysteine 247 (C247) with reduced thioredoxin to inhibit the anti-oxidative properties of thioredoxin. However, the physiological significance of the Txnip-thioredoxin interaction remains largely undefined in vivo.ObjectiveA single mutation of Txnip, C247S, abolishes the binding of Txnip with thioredoxin. Using a conditional and inducible approach with a mouse model of a mutant Txnip that does not bind thioredoxin, we tested whether the interaction of thioredoxin with Txnip is required for Txnip's pro-oxidative or cytotoxic effects in the heart.Methods and resultsOverexpression of Txnip C247S in cells resulted in a reduction in ROS, due to an inability to inhibit thioredoxin. Hypoxia (1% O2, 24 h)-induced killing effects of Txnip were decreased by lower levels of cellular ROS in Txnip C247S-expressing cells compared with wild-type Txnip-expressing cells. Then, myocardial ischemic injuries were assessed in the animal model. Cardiomyocyte-specific Txnip C247S knock-in mice had better survival with smaller infarct size following myocardial infarction (MI) compared to control animals. The absence of Txnip's inhibition of thioredoxin promoted mitochondrial anti-oxidative capacities in cardiomyocytes, thereby protecting the heart from oxidative damage induced by MI. Furthermore, an unbiased RNA sequencing screen identified that hypoxia-inducible factor 1 signaling pathway was involved in Txnip C247S-mediated cardioprotective mechanisms.ConclusionTxnip is a cysteine-containing redox protein that robustly regulates the thioredoxin system via a disulfide bond-switching mechanism in adult cardiomyocytes. Our results provide the direct in vivo evidence that regulation of redox state by Txnip is a crucial component for myocardial homeostasis under ischemic stress.

Project description:Long noncoding RNAs (lncRNAs) are non-protein coding transcripts regulating various critical physiological and pathological processes, yet limited information is available about lncRNAs expression in acute myocardial infarction (AMI). We aimed to identified differentially expressed lncRNAs in blood samples of patients with AMI to assess their diagnostic value. Differential expression of lncRNAs in peripheral blood mononuclear cells (PBMC) of patients with non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI) was compared by RNA sequencing method and validated by real-time polymerase chain reaction (PCR). The area under the receiver operating characteristic curve (ROC) was used to evaluate diagnostic accuracy. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of lncRNA-coexpressed mRNAs were conducted to determine the related biological modules and pathological pathways. RNA sequencing data showed that 58 lncRNAs were differentially expressed between NSTEMI patients and STEMI patients, including 42 upregulated lncRNAs and 16 down-regulated lncRNAs. The ROC curves showed that ENST00000508020.2, LNC_001265, LNC_001526, and LNC_002674 could distinguish AMI patients with preferable sensitivity and specificity. GO enrichment analysis of lncRNA-coexpressed mRNAs indicated that the biological modules were correlated with cell adhesion, calcium ion homeostasis, complement receptor mediated signaling pathway, and immune system process. KEGG pathway analysis indicated that the lncRNAs-co-expressed mRNAs were involved in the regulation of peroxisome proliferators-activated receptors (PPAR) signaling pathway, mTOR signaling pathway, Insulin signaling pathway, HIF-1 signaling, and chemokin signaling pathway. Our results are in line with the previous findings, suggesting that differential expression of lncRNAs would be helpful to understand the molecular mechanism of AMI and might be useful biomarkers for noninvasive diagnostic application. Further studies are still needed to verify our findings and hypothesis.

Project description:BackgroundAcute myocardial infarction (AMI) has two clinical characteristics: high missed diagnosis and dysfunction of leukocytes. Transcriptional RNA on leukocytes is closely related to the course evolution of AMI patients. We hypothesized that transcriptional RNA in leukocytes might provide potential diagnostic value for AMI. Integration machine learning (IML) was first used to explore AMI discrimination genes. The following clinical study was performed to validate the results.MethodsA total of four AMI microarrays (derived from the Gene Expression Omnibus) were included in bioanalysis (220 sample size). Then, the clinical validation was finished with 20 AMI and 20 stable coronary artery disease patients (SCAD). At a ratio of 5:2, GSE59867 was included in the training set, while GSE60993, GSE62646, and GSE48060 were included in the testing set. IML was explicitly proposed in this research, which is composed of six machine learning algorithms, including support vector machine (SVM), neural network (NN), random forest (RF), gradient boosting machine (GBM), decision trees (DT), and least absolute shrinkage and selection operator (LASSO). IML had two functions in this research: filtered optimized variables and predicted the categorized value. Finally, The RNA of the recruited patients was analyzed to verify the results of IML.ResultsThirty-nine differentially expressed genes (DEGs) were identified between controls and AMI individuals from the training sets. Among the thirty-nine DEGs, IML was used to process the predicted classification model and identify potential candidate genes with overall normalized weights > 1. Finally, two genes (AQP9 and SOCS3) show their diagnosis value with the area under the curve (AUC) > 0.9 in both the training and testing sets. The clinical study verified the significance of AQP9 and SOCS3. Notably, more stenotic coronary arteries or severe Killip classification indicated higher levels of these two genes, especially SOCS3. These two genes correlated with two immune cell types, monocytes and neutrophils.ConclusionAQP9 and SOCS3 in leukocytes may be conducive to identifying AMI patients with SCAD patients. AQP9 and SOCS3 are closely associated with monocytes and neutrophils, which might contribute to advancing AMI diagnosis and shed light on novel genetic markers. Multiple clinical characteristics, multicenter, and large-sample relevant trials are still needed to confirm its clinical value.

Dataset Information

Differential Expression of TXNIP Isoforms in the Peripheral Leukocytes of Patients with Acute Myocardial Infarction.

Publications

Differential Expression of TXNIP Isoforms in the Peripheral Leukocytes of Patients with Acute Myocardial Infarction.

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