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

Sci Transl Med. 2019 Sep 18;11(510):eaav5055. doi: 10.1126/scitranslmed.aav5055. | PubMed

Ioannis Akoumianakis¹, Fabio Sanna¹, Marios Margaritis¹, Ileana Badi¹, Nadia Akawi¹, Laura Herdman¹, Patricia Coutinho¹, Harry Fagan¹, Alexios S Antonopoulos¹, Evangelos K Oikonomou¹, Sheena Thomas¹, Amy P Chiu¹, Surawee Chuaiphichai¹, Christos P Kotanidis¹, Constantinos Christodoulides², Mario Petrou³, George Krasopoulos³, Rana Sayeed³, Lei Lv¹, Ashley Hale¹, Meisam Naeimi Kararoudi¹, Eileen McNeill¹, Gillian Douglas¹, Sarah George⁴, Dimitris Tousoulis⁵, Keith M Channon¹, Charalambos Antoniades⁶

1. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.
2. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, OX3 7LE, UK.
3. Department of Cardiothoracic Surgery, Oxford University Hospitals NHS Trust, Oxford, OX3 9DU, UK.
4. Bristol Medical School, University of Bristol, Research Floor Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
5. Cardiology Department, Athens University Medical School, Athens 115 27, Greece.
6. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK. antoniad@well.ox.ac.uk.

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.

Presented By Ioannis Akoumianakis