Wnt signaling in cardiovascular disease: Opportunities and challenges

Austin Gay, Dwight A. Towler

Research output: Contribution to journalReview article

24 Citations (Scopus)

Abstract

Purpose of review 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. Recent findings Both canonical (b-catenin-dependent) and noncanonical (b-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. Summary 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.

Original languageEnglish (US)
Pages (from-to)387-396
Number of pages10
JournalCurrent Opinion in Lipidology
Volume28
Issue number5
DOIs
StatePublished - Oct 1 2017

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Vascular Smooth Muscle
Cardiovascular Diseases
Catenins
Wnt Receptors
LDL-Receptor Related Proteins
Frizzled Receptors
Inflammation
Prediabetic State
Foam Cells
Bone Remodeling
LDL Receptors
Reperfusion Injury
Epigenomics
Methylation
Smooth Muscle Myocytes
Aneurysm
Insulin Resistance
Skeletal Muscle
Homeostasis
Blood Platelets

Keywords

  • dickkopf
  • frizzled
  • low-density lipoprotein receptor-related protein
  • sclerostin
  • Wnt

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Molecular Biology
  • Genetics
  • Nutrition and Dietetics
  • Cardiology and Cardiovascular Medicine
  • Cell Biology

Cite this

Wnt signaling in cardiovascular disease : Opportunities and challenges. / Gay, Austin; Towler, Dwight A.

In: Current Opinion in Lipidology, Vol. 28, No. 5, 01.10.2017, p. 387-396.

Research output: Contribution to journalReview article

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