Abstract 16407: Mir-145 is Differentially Regulated by Tgfβ1 and Ischemia and Targets Disabled-2 Expression and Wnt/β-Catenin Activity in Myocardium and Mesenchymal Stem Cells
Introduction: The effect of wnt/β-catenin signaling in the response to acute myocardial infarction (AMI) remains controversial. Studies have suggested that wnt/β-catenin signaling affects cardiac stem cell and cardiac myocyte response to ischemia. We have shown that down-regulation of the tumor suppressor Disabled-2 (Dab2) has a critical role in regulating cardiac protein expression in mesenchymal stem cells (MSC) and that this effect is the result of an interaction with members of the wnt/β-catenin signaling pathway.
Objective: Define the molecular mechanisms that regulate Dab2 expression in MSC and its interaction with wnt/β-catenin signaling pathway and determine their relevance in the myocardial response to ischemia.
Results and Methods: Using available databases we identified a highly conserved putative binding sites for miR-145 in the 3’UTR of Dab2. Treatment of MSC with TGFβ1 led to rapid and sustained up-regulation of miR-145, down-regulation of Dab2 and up-regulation of β-catenin activity. Gain and loss of function studies show miR-145 up regulation is required for the down-regulation of Dab2 in response to TGFβ1, and that Dab2 down-regulation by miR-145 is required for miR-145 mediated modulation of β-catenin activity. In vivo AMI in rats led to increased cardiac myocyte Dab2 expression as early as 30 min after LAD ligation that was sustained for at least 6 months after. Correspondingly, increases in myocardial Dab2 correlated with the down-regulation of myocardial miR-145 expression following AMI.
Conclusions: Our data demonstrate a novel and critical role for miR-145 expression as a regulator of Dab2 expression and β-catenin activity in response to TGFβ1 in MSC and ischemia in AMI, and identify distinct strategies for up-regulating and down-regulating miR-145. These data identify novel myocardial biology for Dab2 and miR-145 for stem cell based repair and cardiac myocyte response to AMI. Future studies will determine the therapeutic potential for modulation of Dab2 to improve cardiac function in AMI and heart failure.
- © 2011 by American Heart Association, Inc.