Abstract
Mutations in Wnt-signaling coreceptor LRP6 have been linked to coronary artery disease (CAD) by unknown mechanisms. Here, we show that reduced LRP6 activity in LRP6(R611C) mice promotes loss of vascular smooth muscle cell (VSMC) differentiation, leading to aortic medial hyperplasia. Carotid injury augmented these effects and led to partial to total vascular obstruction. LRP6(R611C) mice on high-fat diet displayed dramatic obstructive CAD and exhibited an accelerated atherosclerotic burden on LDLR knockout background. Mechanistically, impaired LRP6 activity leads to enhanced non-canonical Wnt signaling, culminating in diminished TCF7L2 and increased Sp1-dependent activation of PDGF signaling. Wnt3a administration to LRP6(R611C) mice improved LRP6 activity, led to TCF7L2-dependent VSMC differentiation, and rescued post-carotid-injury neointima formation. These findings demonstrate the critical role of intact Wnt signaling in the vessel wall, establish a causal link between impaired LRP6/TCF7L2 activities and arterial disease, and identify Wnt signaling as a therapeutic target against CAD.
Highlights
Aberrant Wnt signaling is implicated in pathogenesis of coronary artery disease and its metabolic risk factors
The canonical Wnt signaling pathway consists of a cascade of events that initiate after binding of a Wnt-protein ligand to a Frizzled family receptor and phosphorylation of its coreceptors LRP5/6
vascular smooth muscle cell (VSMC) cultured from mice homozygote for LRP6R611C mutation exhibited reduced LRP6 activity measured by LRP6 phosphorylation levels and resulted in impaired canonical Wnt signaling activity, manifested by reduced expression of its downstream target cyclin D1 mRNA (Fig. 1A and B)
Summary
Aberrant Wnt signaling is implicated in pathogenesis of coronary artery disease and its metabolic risk factors. The canonical Wnt signaling pathway consists of a cascade of events that initiate after binding of a Wnt-protein ligand to a Frizzled family receptor and phosphorylation of its coreceptors LRP5/6. This leads to stabilization of β Catenin and its translocation to the nucleus, where it interacts with TCF/LEF family transcriptional activators to promote gene expression that regulates cell cycle, cell growth and proliferation. Wnt proteins activate different βcatenin independent signaling pathways that are collectively referred to as non-canonical Wnt signaling. This pathway involves activation of CAMKII, JNK, Rho, Rac, and ROCK. Recent studies suggest that canonical and non-canonical pathways reciprocally inhibit each other and exert opposing effects on common targets such as TCF7L2
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