Abstract 17179: Uremic Toxins Contribute to Cardiac Fibrosis after Myocardial Infarction: Role of MicroRNAs
Introduction: A decline in renal function is a common consequence of myocardial infarction (MI) resulting in increased cardiovascular events, known as cardiorenal syndrome (CRS). Although molecular mechanisms contributing to CRS are not well understood, a role for elevated plasma levels of the uremic toxin indoxyl sulphate (IS) and increased fibrosis have been described. MicroRNAs are small endogenously transcribed regulatory RNAs that modulate gene expression and regulate many cardiac processes involved in cardiac dysfunction.
Aim: Using a rat model we investigated whether MI leads to changes in expression of cardiac microRNA-21 and microRNA-29, both known to contribute to fibrosis. We also investigated the effect of lowering plasma uremic toxins on cardiac expression of these microRNAs.
Methods: MI was induced by coronary artery ligation in male Sprague-Dawley rats. At 16 weeks cardiac function was measured prior to sacrifice. Cardiac tissues were assessed for molecular changes using real-time PCR, western blot analysis and histological methods.
Results: MI significantly increased cardiac microRNA-21, collagen1A1, fibronectin-1 and TGFβ1 mRNA expression, as well as cardiac fibrosis and collagen 1 protein expression. Conversely, microRNA-29 expression was reduced in the heart (Table). Treatment with the AST-120 significantly reversed all these changes (Table). MicroRNA-21 levels significantly correlated with mRNA for TGF-β1 (P=0.049; r2=0.17) and its target genes collagen1A1 (P=0.004; r2=0.35) and fibronectin-1 (P=0.003; r2=0.52). MicroRNA-29b levels negatively and significantly correlated with TGF-β1 (P=0.017; r2=0.26) and collagen1A1 (P=0.048; r2=0.18) and fibronectin-1 (P=0.013; r2=0.29).
Conclusions: We report a link between the beneficial effects of lowering circulating uremic toxins and microRNAs changes in the heart. Targeting microRNA’s may provide a therapeutic target for the treatment of CRS.
Author Disclosures: I. Rana: None. A. Kompa: None. J. Skommer: None. S. Lekawanvijit: None. D.J. Kelly: None. H. Krum: None. F.J. Charchar: None.
- © 2014 by American Heart Association, Inc.