Abstract 234: Transcriptional Profiling of Neuregulin-Induced Myocardial Recovery After Infarction in Rats and Swine
| Autor: | Cristi L Galindo, Abigail Murphy, Michael Hill, John Cleator, Ehab Kasasbeh, Anthony O Caggiano, Tom Parry, Douglas B Sawyer |
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| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | Circulation Research. 111 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | Neuregulin-1 (NRG-1) mediates cell-cell interactions and is a critical growth and developmental signaling molecule in the heart. We have been examining whether the recombinant NRG-1 isoform known as glial growth factor 2 (GGF2) has therapeutic potential for heart failure. In rats and swine with experimental myocardial infarction we have found that GGF2 treatment improves myocardial function and limits progressive myocardial remodeling. To understand potential mechanisms for this effect, we compared gene expression in these animals using microarrays. In rats we compared Sham operated, MI treated with vehicle, and MI treated with GGF2 at a single dose. We found that GGF2 treatment was associated with correction of mitochondrial and metabolic genes altered by MI compared to Sham-operated rats. When compared to 9 published datasets of ∼400 samples from rodents and human heart failure, we identified 563 genes associated with heart failure that were also reversed in expression in response to GGF2. Ingenuity pathway analysis demonstrated clusters of genes associated with energy production and cardiovascular tissue development as particularly enriched in GGF2-treated versus untreated MI rats. In swine our analysis was confined to animals with MI +/- GGF2 treatment at two doses. There were 527 genes altered by GGF2 at both doses compared to untreated controls, with a clear GGF2 dose response. Transcripts altered in response to GGF2 treatment were mainly those associated with extracellular matrix structure and function, MAPK signaling, and p53-mediated apoptosis. Electron microscopy of remote infarct left ventricular tissue from swine confirmed extreme morphological differences in mitochondria from GGF2-treated and vehicle-treated control pigs. Most striking was recovery of intercalated discs in response to GGF2, compared to severe disruption of intercalated disc structures in vehicle-treated control animals. |
| Databáze: | OpenAIRE |
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