Adipose tissue-derived WNT5A regulates vascular redox signaling in obesity via USP17//RAC1-mediated activation of NADPH oxidases
Autor: | Eileen McNeill, Constantinos Christodoulides, Alexios S. Antonopoulos, Patricia Coutinho, Harry Fagan, Ashley B. Hale, Dimitris Tousoulis, Marios Margaritis, Evangelos Oikonomou, Christos P Kotanidis, George Krasopoulos, Lei Lv, Nadia Akawi, Keith M. Channon, Fabio Sanna, Rana Sayeed, Sheena Thomas, L Herdman, Gillian Douglas, Amy P. Chiu, Meisam Naeimi Kararoudi, Sarah J George, Ioannis Akoumianakis, Surawee Chuaiphichai, Ileana Badi, Charalambos Antoniades, Mario Petrou |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
rac1 GTP-Binding Protein Frizzled Vascular smooth muscle Myocytes Smooth Muscle Adipokine Adipose tissue RAC1 030204 cardiovascular system & hematology medicine.disease_cause Ligands Muscle Smooth Vascular Wnt-5a Protein Article 03 medical and health sciences Paracrine signalling 0302 clinical medicine Cell Movement Endopeptidases medicine Animals Obesity Vascular Diseases Adaptor Proteins Signal Transducing Chemistry Wnt signaling pathway NADPH Oxidases General Medicine Arteries Atherosclerosis Oxidants Cell biology Enzyme Activation Mice Inbred C57BL 030104 developmental biology Adipose Tissue embryonic structures Blood Vessels sense organs Oxidation-Reduction Oxidative stress Signal Transduction |
Zdroj: | Sci Transl Med Akoumianakis, I, Sanna, F, Margaritis, M, Badi, I, Akawi, N, Herdman, L, Coutinho, P, Fagan, H, Antonopoulos, A S, Oikonomou, E K, Thomas, S, Chiu, A P, Chuaiphichai, S, Kotanidis, C P, Christodoulides, C, Petrou, M, Krasopoulos, G, Sayeed, R, Lv, L, Hale, A, Naeimi Kararoudi, M, McNeill, E, Douglas, G, George, S, Tousoulis, D, Channon, K M & Antoniades, C 2019, ' Adipose tissue-derived WNT5A regulates vascular redox signaling in obesity via USP17//RAC1-mediated activation of NADPH oxidases ', Science Translational Medicine, vol. 11, no. 510, eaav5055 . https://doi.org/10.1126/scitranslmed.aav5055 |
Popis: | 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. |
Databáze: | OpenAIRE |
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