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

Ioannis Akoumianakis, Fabio Sanna, Marios Margaritis, Ileana Badi, Nadia Akawi, Laura Herdman, Patricia Coutinho, Harry Fagan, Alexios S. Antonopoulos, Evangelos K. Oikonomou, Sheena Thomas, Amy P. Chiu, Surawee Chuaiphichai, Christos P. Kotanidis, Constantinos Christodoulides, Mario Petrou, George Krasopoulos, Rana Sayeed, Lei Lv, Ashley HaleMeisam Naeimi Kararoudi, Eileen McNeill, Gillian Douglas, Sarah George, Dimitris Tousoulis, Keith M. Channon, Charalambos Antoniades

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

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.

Original languageEnglish
Article numbereaav5055
JournalScience Translational Medicine
Volume11
Issue number510
DOIs
Publication statusPublished - Sept 18 2019
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine

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