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Growth/differentiation factor 1 (GDF1) is a secreted glycoprotein of the transforming growth factor-β (TGF-β) superfamily that mediates cell differentiation events during embryonic development. GDF1 is expressed in several tissues, including the heart. However, the functional role of GDF1 in myocardial infarction (MI)-induced cardiac remodelling and dysfunction is not known. Here, we performed gain-of-function and loss-of-function studies using cardiac-specific GDF1 transgenic (TG) and knockout (KO) mice to determine the role of GDF1 in the pathogenesis of functional and architectural cardiac remodelling after MI, which was induced by surgical left anterior descending coronary artery ligation. Our results demonstrate that overexpression of GDF1 in the heart causes a significant decrease in MI-derived mortality post-MI and leads to attenuated infarct size expansion, left ventricular (LV) dilatation, and cardiac dysfunction at 1 week and 4 weeks after MI injury. Compared with control animals, cardiomyocyte apoptosis, inflammation, hypertrophy, and interstitial fibrosis were all remarkably reduced in the GDF1-TG mice following MI. In contrast, GDF1 deficiency greatly exacerbated the pathological cardiac remodelling response after infarction. Further analysis of the in vitro and in vivo signalling events indicated that the beneficial role of GDF1 in MI-induced cardiac dysfunction and LV remodelling was associated with the inhibition of non-canonical (MEK-ERK1/2) and canonical (Smad) signalling cascades. Overall, our data reveal that GDF1 in the heart is a novel mediator that protects against the development of post-infarction cardiac remodelling via negative regulation of the MEK-ERK1/2 and Smad signalling pathways. Thus, GDF1 may serve as a valuable therapeutic target for the treatment of MI., (Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)