Abstract
Background: Bone Morphogenetic Proteins (BMPs) regulate diverse cellular functions during foetal development and postnatal life. Growth Differentiation Factor 5 (GDF5 a.k.a. BMP-14) is a BMP, which is expressed in a variety of tissues including heart. We previously showed that cardiac GDF5 mRNA levels are elevated after experimental myocardial infarction (MI) caused by permanent left anterior descending coronary artery (LAD) ligation. However, the significance of this finding was not known. Methods & Results: GDF5 knock-out (KO; n = 18 for MI) and wild-type (WT; n = 18 for MI) littermate controls were subjected to chronic LAD ligation in order to investigate the consequences resulting from the loss of GDF5 signalling following MI. At 28 days post-LAD ligation or sham (n = 12 for KO; n = 10 for WT), invasive hemodynamic parameters of cardiac function were examined just prior to sacrifice. Histopathology was assessed by morphometric analyses of perfusion fixed hearts and subsequent immunostaining. At 28 days post-MI, GDF5-KO mice exhibited decreased left ventricular systolic pressure and peak positive- and negative- dP/dt , and increased heart rate as compared to WT littermates ( P < 0.005 for each parameters). GDF5-KO mice also exhibited a significant increase in the area, length and transmural expansion of the infarct, scar thinning and cardiac dilatation ( P < 0.05 for each parameter). In addition, GDF5-KO mice displayed significantly fewer myocardial vessels in the infarct and peri-infarct regions as compared to WT littermates ( P < 0.05) . To explore mechanisms underlying this phenotype, we assessed gene expression levels of relevant potential downstream targets of GDF5. At 7d post-MI, quantitative RT-PCR revealed a significant reduction (35%) in VEGF mRNA levels in hearts of KO (n = 6) as compared to WT mice (n = 5, P = 0.033). Summary & Conclusion: These data suggest that increased GDF5 expression observed in hearts after MI plays an important role in cardiac remodelling. Absence of GDF5 expression in KO mice confers detrimental effects on healing and repair of myocardial and vascular tissues after MI. Regulated levels of GDF5, a BMP family member, play an important role in the repair process following cardiac injury.
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