Defective Wnt Signaling: A Potential Contributor to Cardiometabolic Disease?

Hypertension is a major public health problem associated with the increased risk for heart disease and stroke, leading causes of death worldwide. Despite recent treatment advances, hypertension remains present in approximately one-third of adults in the U.S. (1). The majority of hypertensive subjects are now obese and many suffer from insulin resistance, which exacerbates the risk for cardiovascular disease. While there is a well-established clinical association, the mechanisms linking hypertension and insulin resistance are not fully understood. A better understanding of hypertension mechanisms and related metabolic comorbidities will improve targeted treatment approaches and health-related outcomes in this disease.Aberrant Wnt pathway signaling may be one such mechanism linking hypertension, obesity, and type 2 diabetes. The Wnt family of secreted glycoprotein ligands is highly implicated in embryonic development and regulates numerous physiological processes including body axis patterning and cellular adhesion, migration, and differentiation. As shown in Fig. 1, in the canonical pathway (2), Wnt proteins bind the Frizzled G-protein–coupled receptor and coreceptors, such as LDL receptor–related protein (LRP) 5 and 6. Activation of these receptors signals the intracellular phosphoprotein Dishevelled to traffic the destruction complex (including glycogen synthase kinase 3β [GSK-3β]) to the plasma membrane. This allows for stabilization and translocation of β-catenin to the nucleus to coactivate T-cell factor (TCF) and lymphoid enhancing factor transcription factors. Noncanonical Wnt pathways, which are independent of β-catenin, have also been identified and play a role in the regulation of cell polarity and …