Increased m6A-RNA methylation and FTO suppression is associated with myocardial inflammation and dysfunction during endotoxemia in mice
Autor: | Praveen K Dubey, Prasanna Krishnamurthy, Mallikarjun Patil, Sarojini Singh, Shubham Dubey, Paras Ahuja, Suresh K Verma |
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Rok vydání: | 2021 |
Předmět: |
Lipopolysaccharides
medicine.medical_specialty Lipopolysaccharide RNA methylation Clinical Biochemistry Alpha-Ketoglutarate-Dependent Dioxygenase FTO Proinflammatory cytokine Cell Line chemistry.chemical_compound Mice Downregulation and upregulation Internal medicine medicine Animals RNA Processing Post-Transcriptional Molecular Biology Inflammation Gene knockdown biology Chemistry Myocardium Cell Biology General Medicine Methylation Endotoxemia Myocarditis Endocrinology DNA methylation biology.protein Demethylase |
Zdroj: | Molecular and cellular biochemistry. 477(1) |
ISSN: | 1573-4919 |
Popis: | Endotoxemia triggers life-threatening immune and cardiovascular response that leads to tissue damage, multi-organ failure, and death. The understanding of underlying molecular mechanisms is still evolving. N6-methyladenosine (m6A)-RNA modification plays key regulatory role in numerous biological processes. However, it remains unclear whether endotoxemia alters RNA methylation in the myocardium. In the current study, we investigated the effect of lipopolysaccharide (LPS)-induced endotoxemia on m6A-RNA methylation and its implications on myocardial inflammation and left ventricular (LV) function. Following LPS administration, mice showed increases in m6A-RNA methylation in the myocardium with a corresponding decrease in the expression of fat mass and obesity-associated protein (FTO, an m6A eraser/demethylase). The changes were associated with a significant increase in expression of myocardial inflammatory cytokine genes, such as IL-6, TNF-α, IL-1β, and reduced LV function. Moreover, rat cardiomyoblasts (H9c2) exposed to LPS showed similar changes (with increase in m6A-RNA methylation and inflammatory cytokine genes, whereas downregulation of FTO). Furthermore, methylated RNA immunoprecipitation assay showed hypermethylation and increase in the expression of IL-6 and TNF-α genes in LPS-treated H9c2 cells as compared to untreated cells. Interestingly, FTO knockdown in cardiomyocytes mimicked the above effects. Taken together, these data suggest that endotoxemia-induced m6A methylation might play a critical role in expression of cardiac proinflammatory cytokines, and modulation of m6A methylation might limit myocardial inflammation and dysfunction during endotoxemia. |
Databáze: | OpenAIRE |
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