Adipose tissue-derived WNT5A regulates vascular redox signaling in obesity via USP17/RAC1-mediated activation of NADPH oxidases
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
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, OX3 7LE, UK.
- Department of Cardiothoracic Surgery, Oxford University Hospitals NHS Trust, Oxford, OX3 9DU, UK.
- Bristol Medical School, University of Bristol, Research Floor Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
- Cardiology Department, Athens University Medical School, Athens 115 27, Greece.
- 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