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Wnt signaling in cardiovascular disease: opportunities and challenges.
Authors Gay A, Towler DA
Submitted By Dwight Towler on 8/29/2017
Status Published
Journal Current opinion in lipidology
Year 2017
Date Published 7/1/2017
Volume : Pages Not Specified : Not Specified
PubMed Reference
Abstract Cardiometabolic diseases increasingly afflict our aging, dysmetabolic
population. Complex signals regulating low-density lipoprotein receptor-related
protein (LRP) and frizzled protein family members - the plasma membrane
receptors for the cadre of Wnt polypeptide morphogens - contribute to the
control of cardiovascular homeostasis., Both canonical (脽-catenin-dependent) and
noncanonical (脽-catenin-independent) Wnt signaling programs control vascular
smooth muscle (VSM) cell phenotypic modulation in cardiometabolic disease. LRP6
limits VSM proliferation, reduces arteriosclerotic transcriptional
reprogramming, and preserves insulin sensitivity while LRP5 restrains foam cell
formation. Adipose, skeletal muscle, macrophages, and VSM have emerged as
important sources of circulating Wnt ligands that are dynamically regulated
during the prediabetes-diabetes transition with cardiometabolic consequences.
Platelets release Dkk1, a LRP5/LRP6 inhibitor that induces endothelial
inflammation and the prosclerotic endothelial-mesenchymal transition. By
contrast, inhibitory secreted frizzled-related proteins shape the Wnt signaling
milieu to limit myocardial inflammation with ischemia-reperfusion injury. VSM
sclerostin, an inhibitor of canonical Wnt signaling in bone, restrains
remodeling that predisposes to aneurysm formation, and is downregulated in
aneurysmal vessels by epigenetic methylation., Components of the Wnt signaling
cascade represent novel targets for pharmacological intervention in
cardiometabolic disease. Conversely, strategies targeting the Wnt signaling
cascade for other therapeutic purposes will have cardiovascular consequences
that must be delineated to establish clinically useful
pharmacokinetic-pharmacodynamic relationships.

Complications