Alpha-1 antitrypsin deficiency: From the lung to the heart?

Ivan, Cristina; Imboden, Medea; Bettschart, Robert; Caviezel, Seraina; Dratva, Julia; Pons, Marco; Rothe, Thomás; Schmidt‐Trucksäss, Arno; Stolz, Daiana; Thun, Gian Andri; Eckardstein, Arnold von; Kronenberg, Florian; Ferrarotti, Ilaria; Probst‐Hensch, Nicole

doi:10.1016/j.atherosclerosis.2018.01.042

Cited by 21 publications

(13 citation statements)

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“…concentrations of A1AT change during a disease or in response to inflammation or tissue injury [14]. A1AT is currently used to treat chronic obstructive pulmonary disease and A1AT deficiency [15,16].…”

Section: Alpha-1-antitrypsinmentioning

confidence: 99%

Elucidating the mechanism of action of alpha-1-antitrypsin using retinal pigment epithelium cells exposed to high glucose. Potential use in diabetic retinopathy

et al. 2020

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Background Alpha-1-antitrypsin is a protein involved in avoidance of different processes that are seen in diabetic retinopathy pathogenesis. These processes include apoptosis, extracellular matrix remodeling and damage of vessel walls and capillaries. Furthermore, because of its antiinflammatory effects, alpha-1-antitrypsin has been proposed as a possible therapeutic approach for diabetic retinopathy. Our group tested alpha-1-antitrypsin in a type 1 diabetes mouse model and observed a reduction of inflammation and retinal neurodegeneration. Thus, shedding light on the mechanism of action of alpha-1-antitrypsin at molecular level may explain how it works in the diabetic retinopathy context and show its potential for use in other retinal diseases. Methods In this work, we evaluated alpha-1-antitrypsin in an ARPE-19 human cell line exposed to high glucose. We explored the expression of different mediators on signaling pathways related to pro-inflammatory cytokines production, glucose metabolism, epithelial-mesenchymal transition and other proteins involved in the normal function of retinal pigment epithelium by RT-qPCR and Western Blot. Results We obtained different expression patterns for evaluated mediators altered with high glucose exposure and corrected with the use of alpha-1-antitrypsin.

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Section: Alpha-1-antitrypsinmentioning

confidence: 99%

Elucidating the mechanism of action of alpha-1-antitrypsin using retinal pigment epithelium cells exposed to high glucose. Potential use in diabetic retinopathy

et al. 2020

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“…SERPINA1 is the most abundant serine protease inhibitor in human blood and exerts anti-inflammatory and immune-modulatory effects. Genetic SERPINA1 deficiency was associated with increased cardiovascular risk (Curjuric et al, 2018). TBC1D9B, a GTPase-activating protein for Rab family protein, positively regulated autophagic flux by interacting with LC3B (Liao et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Weighted Gene Co-Expression Network Analysis Identifies Critical Genes in the Development of Heart Failure After Acute Myocardial Infarction

Niu

Zhang²,

Zhang

et al. 2019

Front. Genet.

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Background: The development of heart failure (HF) remains a common complication following an acute myocardial infarction (AMI), and is associated with substantial adverse outcomes. However, the specific predictive biomarkers and candidate therapeutic targets for post-infarction HF have not been fully established. We sought to perform a weighted gene co-expression network analysis (WGCNA) to identify key modules, hub genes, and possible regulatory targets involved in the development of HF following AMI. Methods: Genes exhibiting the most (top 50%) variation in expression levels across samples in a GSE59867 dataset were imported to the WGCNA. Gene Ontology and pathway enrichment analyses were performed on genes identified in the key module by Metascape. Gene regulatory networks were constructed using the microarray probe reannotation and bioinformatics database. Hub genes were screened out from the key module and validated using other datasets. Results: A total of 10,265 most varied genes and six modules were identified between AMI patients who developed HF within 6 months of follow-up and those who did not. Specifically, the blue module was found to be the most significantly related to the development of post-infarction HF. Functional enrichment analysis revealed that the blue module was primarily associated with the inflammatory response, immune system, and apoptosis. Seven transcriptional factors, including SPI1, ZBTB7A, IRF8, PPARG, P65, KLF4, and Fos, were identified as potential regulators of the expression of genes identified in the blue module. Further, non-coding RNAs, including miR-142-3p and LINC00537, were identified as having close interactions with genes from the blue module. A total of six hub genes (BCL3, HCK, PPIF, S100A9, SERPINA1, and TBC1D9B) were identified and validated for their predictive value in identifying future HFs. Conclusions: By using the WGCNA, we provide new insights into the underlying molecular mechanism and molecular markers correlated with HF development following an AMI, which may serve to improve risk stratification, therapeutic decisions, and prognosis prediction in AMI patients.

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“…The biological mechanisms by which occupational silica exposure could increase the risk of heart disease are not well understood. Coal dust may cause upregulation of leucocyte recruiting factors and damage of alpha-1-antitrypsin (A1AT),43 while relative elevations in leucocyte count and A1AT deficiency are associated with increased cardiovascular risk 44 45. Moreover, silica might induce inflammation, which plays a key role in coronary artery disease 46 47…”

Section: Discussionmentioning

confidence: 99%

Occupational exposure to silica and risk of heart disease: a systematic review with meta-analysis

Liu

Fang

et al. 2020

BMJ Open

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ObjectiveTo search for evidence of the relationship between occupational silica exposure and heart disease.DesignA systematic review and meta-analysis.BackgroundGrowing evidence suggests a relationship between occupational silica exposure and heart disease; however, the link between them is less clear.Data sourcesPubMed, ScienceDirect, Springer and EMBASE were searched for articles published between 1 January 1995 and 20 June 2019. Articles that investigated the effects of occupational silica exposure on the risk of heart disease were considered.Study selectionWe included cohort studies, including prospective, retrospective and retroprospective studies.Data extraction and synthesisWe extracted data using a piloted data collection form and conducted random-effects meta-analysis and exposure-response analysis. The meta-relative risk (meta-RR), a measure of the average ratio of heart disease rates in those with and without silica exposure, was used as an inverse variance-weighted average of relative risks from the individual studies. The Newcastle-Ottawa Quality Assessment Scale for cohort studies was used for study quality assessment.Outcome measureWe calculated the risk of heart diseases such as pulmonary heart disease, ischaemic heart disease and others.ResultsTwenty cohort studies were included. The results suggest a significant increase in the risk of overall heart disease (meta-RR=1.08, 95% CI 1.03 to 1.13). Stronger evidence of association with pulmonary heart disease was found in the risk estimate of both categories of heart disease (meta-RR=1.24, 95% CI 1.08 to 1.43) and in the exposure-response analysis (meta-RR=1.39, 95% CI 1.19 to 1.62). Our subgroup analyses also revealed that the statistical heterogeneity among studies could be attributed mainly to the diversity in reference group, occupation and study quality score.ConclusionsSilica-exposed workers are at an increased risk for overall heart disease, especially pulmonary heart disease. Further research is needed to better clarify the relationship between occupational silica exposure and ischaemic heart disease.PROSPERO registration numberCRD42019124673.

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Alpha-1 antitrypsin deficiency: From the lung to the heart?

Cited by 21 publications

References 37 publications

Elucidating the mechanism of action of alpha-1-antitrypsin using retinal pigment epithelium cells exposed to high glucose. Potential use in diabetic retinopathy

Elucidating the mechanism of action of alpha-1-antitrypsin using retinal pigment epithelium cells exposed to high glucose. Potential use in diabetic retinopathy

Weighted Gene Co-Expression Network Analysis Identifies Critical Genes in the Development of Heart Failure After Acute Myocardial Infarction

Occupational exposure to silica and risk of heart disease: a systematic review with meta-analysis

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