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Adipose tissue-derived WNT5A regulates vascular redox signaling in obesity via USP17/RAC1-mediated activation of NADPH oxidases

Lookup NU author(s): Dr Chris Kotanidis

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Abstract

Copyright © 2019 The Authors. 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.

Publication metadata

Author(s): Akoumianakis I, Sanna F, Margaritis M, Badi I, Akawi N, Herdman L, Coutinho P, Fagan H, Antonopoulos AS, Oikonomou EK, Thomas S, Chiu AP, Chuaiphichai S, Kotanidis CP, Christodoulides C, Petrou M, Krasopoulos G, Sayeed R, Lv L, Hale A, Kararoudi MN, McNeill E, Douglas G, George S, Tousoulis D, Channon KM, Antoniades C

Publication type: Article

Publication status: Published

Journal: Science Translational Medicine

Year: 2019

Volume: 11

Issue: 510

Online publication date: 18/09/2019

Acceptance date: 09/08/2019

ISSN (print): 1946-6234

ISSN (electronic): 1946-6242

Publisher: American Association for the Advancement of Science

URL: https://doi.org/10.1126/scitranslmed.aav5055

DOI: 10.1126/scitranslmed.aav5055

PubMed id: 31534019

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