Adipose tissue–derived WNT5A regulates vascular redox signaling in obesity via USP17/RAC1-mediated activation of NADPH oxidases
- 18 September 2019
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 11 (510)
- https://doi.org/10.1126/scitranslmed.aav5055
Abstract
Obesity is associated with changes in the secretome of adipose tissue (AT), which affects the vasculature through endocrine and paracrine mechanisms. Wingless-related integration site 5A (WNT5A) and secreted frizzled-related protein 5 (SFRP5), adipokines that regulate noncanonical Wnt signaling, are dysregulated in obesity. We hypothesized that WNT5A released from AT exerts endocrine and paracrine effects on the arterial wall through noncanonical RAC1-mediated Wnt signaling. In a cohort of 1004 humans with atherosclerosis, obesity was associated with increased WNT5A bioavailability in the circulation and the AT, higher expression of WNT5A receptors Frizzled 2 and Frizzled 5 in the human arterial wall, and increased vascular oxidative stress due to activation of NADPH oxidases. Plasma concentration of WNT5A was elevated in patients with coronary artery disease compared to matched controls and was independently associated with calcified coronary plaque progression. We further demonstrated that WNT5A induces arterial oxidative stress and redox-sensitive migration of vascular smooth muscle cells via Frizzled 2–mediated activation of a previously uncharacterized pathway involving the deubiquitinating enzyme ubiquitin-specific protease 17 (USP17) and the GTPase RAC1. Our study identifies WNT5A and its downstream vascular signaling as a link between obesity and vascular disease pathogenesis, with translational implications in humans.Keywords
Funding Information
- Wellcome Trust (090532/Z/09/Z)
- British Heart Foundation (FS/16/15/32047)
- British Heart Foundation (PG/13/56/30383)
- British Heart Foundation (CH/16/1/32013)
- British Heart Foundation (RG/13/1/30181)
- British Heart Foundation (FS/16/45/32359)
- Novo Nordisk UK Research Foundation (NNF15CC0018486)
- European Commission
This publication has 51 references indexed in Scilit:
- Pro-Inflammatory wnt5a and Anti-Inflammatory sFRP5 Are Differentially Regulated by Nutritional Factors in Obese Human SubjectsPLOS ONE, 2012
- Rapid, Direct Effects of Statin Treatment on Arterial Redox State and Nitric Oxide Bioavailability in Human Atherosclerosis via Tetrahydrobiopterin-Mediated Endothelial Nitric Oxide Synthase CouplingJournal of the American College of Cardiology, 2011
- A Rapid and Scalable System for Studying Gene Function in Mice Using Conditional RNA InterferenceCell, 2011
- The deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motilityNature Communications, 2011
- Sfrp5 Is an Anti-Inflammatory Adipokine That Modulates Metabolic Dysfunction in ObesityScience, 2010
- The Deubiquitinating Enzyme USP17 Is Highly Expressed in Tumor Biopsies, Is Cell Cycle Regulated, and Is Required for G1-S ProgressionCancer Research, 2010
- Basic Mechanisms of Oxidative Stress and Reactive Oxygen Species in Cardiovascular InjuryTrends in Cardiovascular Medicine, 2007
- 2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)European Heart Journal, 2006
- Obesity and Systemic Oxidative StressArteriosclerosis, Thrombosis, and Vascular Biology, 2003
- A new mathematical model for relative quantification in real-time RT-PCRNucleic Acids Research, 2001