Abstract 255: Hur/ppar-gamma Mediates Posttranscriptional Regulation of Hyperglycemia-induced Pro-inflammatory Response
Metabolic disorders including diabetes and obesity are associated with persistent activation of the innate immune response, which leads to low-grade inflammation and increased cardiovascular risk. The RNA-binding protein HuR binds to and post-transcriptionally regulates inflammatory cytokines, mRNA stability and gene expression, although it’s exact role in the diabetic condition remains unclear. Bone marrow-derived macrophages (BMM) exposed to high glucose (HG, 25mM D-glucose) displayed elevated expression of HuR and reduced expression of nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) as compared to low glucose (LG, 5mM D-glucose)-treated cells. The increase in HuR expression was associated with an increase in the gene expression of various inflammatory cytokines including TNF-alpha, MCP-1, IL-1beta and IL-6. At the molecular level, macrophages activated with LPS showed enhancements in expression of inflammatory mRNAs and also promoted their stability. Conversely, knockdown of HuR induced post-transcriptional silencing, reduced the mRNA stability and expression of inflammatory cytokines. Macrophages treated with selective antagonists of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma), GW9662 displayed increases in HuR expression and of various inflammatory cytokines. In an in vivo model of myocardial infarction, mice receiving intramyocardial injection of HuR-specific shRNA displayed a reduced inflammatory cytokine profile in the myocardium as compared to control shRNA treated mice. Taken together, these data highlight the role of HuR as a homeostatic coordinator of cytokine mRNA that regulates innate inflammatory effects and demonstrates the potential of modulating the effects of HuR for clinical benefit against pathologic inflammation in diabetes/obesity.
Author Disclosures: S. Suresh Babu: None. R.A. Thandavarayan: None. D. Joladarashi: None. P. Jeyabal: None. S. Krishnamurthy: None. V.N.S. Garikipati: None. S.K. Verma: None. R. Kishore: None. P. Krishnamurthy: None.
This research has received full or partial funding support from the American Heart Association, National Center.
- © 2015 by American Heart Association, Inc.