Abstract 1451: Expression and Signalling of Specific Bone Morphogenetic Proteins in a Mouse Model of Myocardial Infarction
Background: Bone Morphogenetic Proteins (BMPs) and BMP-like Growth Differentiation Factor 5 (GDF5) regulate diverse cellular functions through interactions with BMP and activin receptors. While BMPs have been studied in cardiac development, regulation of BMPs and GDF5 and their potential roles in repair and regeneration following myocardial infarction (MI) have not been explored.
Methods & Results: To investigate the regulation of BMP and GDF5 signalling following MI, mice were subjected to chronic LAD ligation. Hearts were harvested at 2, 4, 7 and 14 days, their anterior (infarct and peri-infarct regions) and posterior ventricular walls were excised and RNA was extracted. Real-Time RT-PCR was performed to quantify expression of GDF5, BMP4 and BMP7 mRNA. Compared to sham-operated mice, BMP4 and GDF5 mRNA were significantly elevated at 7- and 14-days post-LAD ligation in the anterior wall (5 & 4.8 times for BMP4 and 8.5 & 11.6 times for GDF5 vs. sham, n=3, p<0.05). By contrast, BMP7 mRNA remained unchanged at these time points (p=NS). Next, we examined if the angiogenic targets of BMP signalling, the Inhibitor of Differentiation proteins, ID1, ID2 and ID3, were upregulated following MI. Coincident with GDF5 and BMP4, ID2 and ID3 mRNA levels were elevated in the anterior wall of post-MI hearts at 7- and 14-days (3–5 times at these two time points vs. sham). At these time points, ID2 and ID3 protein expression was localized to the nuclei of cardiomyocytes and endothelial cells in the infarct and peri-infarct areas. Nuclear localization of ID proteins suggests that these proteins may interact with basic helix-loop-helix transcription factors and inhibit their regulation of genes involved in differentiation and cell cycle arrest. Furthermore, recombinant GDF5 treatment alone induced the expression of ID2 and ID3 genes in isolated cardiomyocytes as compared to non-treated control cells (2–3 times vs. untreated controls at 2h & 25h after rGDF5 stimulation).
Summary: These data suggest that GDF5- and or BMP4-induced ID2 and ID3 expression in cardiac endothelial cells could promote their proliferation and confer angiogenesis. Hence, BMP signalling by GDF5 and BMP4, via stimulation of ID2 and ID3, may have important implications in cardiac repair following MI.