Purpose: LDL receptor-related protein 5 (LRP5) triggers the canonical Wnt pathway which participates in cell function regulation, spanning from tissue regeneration to lipid metabolism. However there is little understanding on the role of LRP5 in the heart. The aim of this study was to investigate the expression and function of LRP5 and the canonical Wnt signalling pathway in cardiac pathology.
Methods: Myocardial damage and LRP5 and Wnt signalling proteins expression levels were measured in in vivo myocardial infarction (MI) models in LRP5-/- mice and in human dyslipidemic hearts from heart transplants. To characterize the role of LRP5 and the different metabolic pathways involved in myocardial damage post-MI cultured cardiomyocytes, myofibroblasts and endothelial cells were challenged with lipids and hypoxic treatments.
Results: We show that LRP5-/- mice have an increased infarct size after MI with respect to WT mice, indicating a protective role of LRP5 in injured myocardium. Furthermore, administration of a GSK3 inhibitor that activates the Wnt pathway downstream LRP5, induced smaller infarcts in WT and LRP5-/- mice indicating that an active Wnt pathway plays a protective role in injured myocardium. Proteins members and targets of the canonical Wnt signalling pathway were downregulated in the ischemic myocardium of WT mice in the acute phase of MI and regained physiological values after GSK3 inhibitor treatment. Hypoxic treatments induced LRP5 overexpression in isolated cardiomyocytes and endothelial cells indicating that the protective role of LRP5 is produced through these cell types. Administration of hypercholesterolemic diets induced bigger infarcts in WT and LRP5-/- mice. LRP5 overexpression/silencing experiments in isolated cardiomyocytes induced Wnt pathway activation only in lipid-loaded hypoxic cardiomyocytes whereas LRP5-silencing blocked the pathway. Finally, an increased LRP5 and Wnt regulated gene expression in human ischemic failing hearts of dyslipidemic patients, was observed.
Conclusions: Our results demonstrate that the modulation of LRP5 and the canonical Wnt pathway in LRP5-/- mice, in hypoxic cardiomyocytes and in human ischemic myocardium is a defensive pro-survival process of the damaged myocardium triggered to restore cell viability. Therapeutic interventions targeting LRP5 may favour cardiac healing post-MI.