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Increased m6A-RNA methylation and FTO suppression is associated with myocardial inflammation and dysfunction during
Praveen K Dubey1, Mallikarjun Patil1, Sarojini Singh1
1Department of Biomedical Engineering, School of Medicine and School of Engineering, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Abstract:
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.
Insights
Endotoxemia increases N6-methyladenosine (m6A)-RNA methylation in the heart, promoting inflammation and impairing function. Modulating m6A methylation may protect the heart during endotoxemia.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Immunology
Background:
- Endotoxemia causes severe immune and cardiovascular responses, leading to organ damage and death.
- The molecular mechanisms underlying endotoxemia's effects on the heart are not fully understood.
- N6-methyladenosine (m6A)-RNA modification is a key regulator in biological processes, but its role in endotoxemia-induced cardiac dysfunction is unclear.
Purpose of the Study:
- To investigate the impact of lipopolysaccharide (LPS)-induced endotoxemia on m6A-RNA methylation in the myocardium.
- To determine the relationship between altered m6A-RNA methylation and myocardial inflammation and left ventricular (LV) function during endotoxemia.
- To explore the role of the m6A demethylase FTO (fat mass and obesity-associated protein) in endotoxemia-induced cardiac changes.
Main Methods:
- LPS administration to mice to induce endotoxemia.
- Analysis of m6A-RNA methylation levels and FTO expression in mouse myocardium.
- Assessment of myocardial inflammatory cytokine gene expression (IL-6, TNF-α, IL-1β) and LV function.
- In vitro studies using rat cardiomyoblasts (H9c2) exposed to LPS.
- Methylated RNA immunoprecipitation assays in LPS-treated H9c2 cells.
- FTO knockdown experiments in cardiomyocytes.
Main Results:
- LPS-induced endotoxemia increased m6A-RNA methylation in the myocardium and decreased FTO expression.
- These changes correlated with increased expression of inflammatory cytokine genes (IL-6, TNF-α, IL-1β) and reduced LV function.
- Similar alterations in m6A-RNA methylation, FTO expression, and inflammatory gene expression were observed in LPS-treated H9c2 cells.
- Hypermethylation and increased IL-6 and TNF-α gene expression were confirmed in LPS-treated H9c2 cells.
- FTO knockdown in cardiomyocytes replicated the effects of LPS treatment.
Conclusions:
- Endotoxemia significantly alters m6A-RNA methylation in the myocardium.
- Increased m6A-RNA methylation, potentially due to FTO downregulation, contributes to cardiac inflammation and dysfunction during endotoxemia.
- Modulating m6A RNA methylation represents a potential therapeutic strategy to mitigate myocardial inflammation and dysfunction in endotoxemia.
