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A Zebrafish Model of Diabetes Mellitus and Metabolic Memory
Published on: February 28, 2013
The MicroRNAs in the Pathogenesis of Metabolic Memory
Xueyu Zhong1, Yunfei Liao1, Lulu Chen1
1Departments of Endocrinology (X.Z., Y.L., L.C., G.L., T.Z.) and Orthopedics (Y.F.), Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; and Department of Endocrinology (J.Z.), Yichang Central People's Hospital, First Clinical Medical College of Three Gorges University, Yichang 443003, China.
Abstract:
"Metabolic memory" is identified as a phenomenon that previous exposure to hyperglycemia results in the long-lasting deleterious effects on cardiovascular events. More and more researches show that epigenetics plays an important role in the pathogenesis of metabolic memory. It remains unclear whether microRNA (miRNA) dysfunctions participate in the event. In this study, the miRNA arrays on human aortic endothelial cells were adopted to seek the miRNAs that may be involved in the metabolic memory and were verified in vivo and in vitro. Sixteen miRNAs were found differentially expressed. Among these miRNAs, the expressions of miR-125b, miR-146a-5p, and miR-29a-3p were associated with persistent impaired endothelial function and altered proinflammatory gene expressions, including nuclear factor-κB (NF-κB) subunit p65. Direct inhibition of miR-125b expression or increased miR-146a-5p expression blunted NF-κB signals and improved the endothelial function. Luciferase reporter assays confirmed the biochemical relationship for miR-125b targeting on TNF-α-induced protein 3 and miR-146a-5p targeting on TNF receptor-associated factor 6 and IL-1 receptor-associated kinase 1 during the activation of NF-κB pathway. Thus, our findings demonstrate that glucose induced changes in miR-125b and miR-146a-5p are related to the long-lasting activation of NF-κB pathway and contribute to follow-up metabolic memory.
Insights
High blood sugar (hyperglycemia) can cause lasting cardiovascular damage through metabolic memory. This study reveals that microRNAs (miRNAs) like miR-125b and miR-146a-5p are key players in this process by affecting inflammation.
Area of Science:
- Cardiovascular Epigenetics
- Endothelial Cell Biology
- Molecular Medicine
Background:
- Metabolic memory links prior hyperglycemia to persistent cardiovascular risks.
- Epigenetic mechanisms are implicated in metabolic memory pathogenesis.
- The role of microRNAs (miRNAs) in metabolic memory remains largely unexplored.
Purpose of the Study:
- To investigate the involvement of miRNAs in the phenomenon of metabolic memory.
- To identify specific miRNAs and their targets contributing to endothelial dysfunction in metabolic memory.
- To elucidate the molecular pathways linking hyperglycemia, miRNAs, and inflammation.
Main Methods:
- miRNA arrays were used on human aortic endothelial cells to identify differentially expressed miRNAs.
- In vivo and in vitro experiments validated the role of selected miRNAs.
- Luciferase reporter assays were employed to confirm miRNA-target interactions within the NF-κB pathway.
Main Results:
- Sixteen miRNAs showed differential expression; miR-125b, miR-146a-5p, and miR-29a-3p were significantly associated with impaired endothelial function and inflammation.
- Modulation of miR-125b and miR-146a-5p expression directly impacted nuclear factor-κB (NF-κB) signaling and endothelial function.
- Specific targeting of key NF-κB pathway components (TNF-α-induced protein 3, TRAF6, IRAK1) by miR-125b and miR-146a-5p was confirmed.
Conclusions:
- Glucose-induced alterations in miR-125b and miR-146a-5p contribute to sustained NF-κB pathway activation.
- These miRNA dysfunctions are critical mediators of the long-lasting endothelial damage characteristic of metabolic memory.
- Targeting specific miRNAs may offer novel therapeutic strategies for mitigating metabolic memory-associated cardiovascular complications.
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