Novel Insights in Intercellular Communication within the Heart

Background: LDL receptor-related protein 5 (LRP5) triggers the canonical Wnt pathway which participates in cell function regulation, including lipoprotein metabolism, macrophage mobility and phagocytosis, but its function in the heart is unknown. Purpose: The aim of this study was to investigate LRP5 and the canonical Wnt signalling pathway in myocardial injury after acute-myocardial infarction (MI). Methods: MI was induced in WT and LRP5-/mice by coronary ligation. Infarct size, LRP5 and Wnt signalling proteins were measured. LRP5 and the different metabolic pathways involved in myocardial damage post-MI were analyzed in isolated cardiomyocytes, myofibroblasts and endothelial cells. Results: LRP5-/mice have significantly larger infarcts than WT mice (20.8 vs 9.9 p,0.5) suggesting a protective role of LRP5/Wnt in injured myocardium. Furthermore, administration of a GSK3 inhibitor that activates the Wnt pathway downstream LRP5, induced smaller infarcts in LRP5-/mice indicating that an active Wnt pathway plays a protective role in the myocardium. Hypoxia induced LRP5 overexpression in isolated cardiomyocytes and endothelial cells indicating that a defensive and protective expression of LRP5 is triggered in both cell types. Induction of MI in WT and in LRP5-/hypercholesterolemic animals, common risk factor in patients with ACS, induced larger infarcts in both genotypes. In isolated cardiomyocytes, LDL induced LRP5 overexpression and Wnt pathway activation whereas LRP5-silencing blocked the pathway. Conclusions: LRP5 and the canonical Wnt pathway activation is a defensive pro-survival process triggered to protect the ischemic myocardium against different injury triggers, such as hypoxia and hypercholesterolemia to favour and restore cell viability.