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Diabetic cardiomyopathy structurally manifests as cardiomyocyte hypertrophy and interstitial fibrosis, the latter is due to an increased extracellular matrix (ECM) protein production. Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme activated by DNA strand breaks, is involved in several pathogenetic processes in diabetes. In this study, we investigated the role of PARP activation in the production of fibronectin (FN) and its splice variant EDB+ FN, in the heart in diabetes. Diabetes was induced in male Sprague-Dawley rats by IP injection of 65mg/kg streptozotocin (STZ). One group of diabetic animals were treated with 30 mg/kg (IP) of PARP inhibitor 3-aminobenzamide (ABA). After 4 months of treatment, the rats were sacrificed and cardiac tissues were harvested. In a second series of experiments, we used PARP knockout mice and wild type (WT) mice. As PARP knockout mice are resistant to STZ, we induced a hyperhexosemic state by 30% galactose feeding. After two months of follow-up, the mice were sacrificed and the cardiac tissues were collected. The tissues were analyzed for mRNA expression of FN, EDB+ FN and transcriptional co-activator p300. The diabetic animals showed hyperglycemia and reduced body weight gain. The cardiac tissues from the diabetic rats demonstrated increased mRNA expression of FN, EDB+ FN and p300 genes. PARP blockade by ABA prevented such upregulation. Similarly, galactose feeding caused augmented production of FN, EDB+ FN and p300 mRNA in the heart of WT mice. Such upregulation were also prevented in the PARP knockout mice on galactose. The cardiac tissues of WT mice on galactose further showed presence of increased interstitial fibrosis. The data from this study suggests that, in diabetes, PARP activation may modulate increased FN and EDB+ FN production in the heart via a p300-dependent mechanism. A similar mechanism is also important in the heart of galactose-fed animals. These studies were supported by grants from the Canadian Institute of Health Research and the Heart and Stroke Foundation of Ontario. [ABSTRACT FROM AUTHOR]