Therapeutic Targeting of LRP6 in Cardiovascular Diseases: Challenging But Not Wnt-Possible!

Coronary artery disease (CAD), often related to dyslipidemia, is a major cause of death worldwide, highlighting unmet therapeutic needs. Lipoprotein receptor-related protein 6 (LRP6) is a member of the low-density lipoprotein receptor (LDLR) family composed of structurally related cell surface receptors and acts, in consort with Frizzled receptors, as a coreceptor to mediate the Wnt/β-catenin signalling pathway. Impaired LRP6 signalling in humans has been associated with multiple cardiovascular risk factors such as elevated serum LDL, triglycerides, and glucose levels. Considerable efforts have been deployed to better understand the underlying mechanisms of LRP6-associated disorders, and the therapeutic targeting of LRP6 has been demonstrated to have positive effects in various animal models of cardiovascular disease. This review presents a synthetic summary highlighting the major roles of LRP6. LRP6 regulates a multitude of cellular mechanisms dependently or independently of the β-catenin pathway, as LRP6 activates gene transcription, regulates crucial cellular events such as cell cycle or protein synthesis, and even modulates gap junctional coupling in cardiomyocytes and LDLR recycling in hepatocytes. We discuss the potential contribution of LRP6 as a therapeutic target, as LRP6 inhibition limits myocardial fibrosis and promotes cardiac repair in myocardial infarction, limits neointimal formation in carotid injury models, decreases blood pressure in hypertensive animals, and reduces adipogenesis and lipogenesis to prevent hypercholesterolemia and atherosclerosis. These findings from past studies highlight LRP6 as a key player in the development of heart disease and a promising therapeutic target for cardiovascular disease in humans.