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

被引：94

作者：

Akoumianakis, Ioannis ^{[1
]}

Sanna, Fabio ^{[1
]}

Margaritis, Marios ^{[1
]}

Badi, Ileana ^{[1
]}

Akawi, Nadia ^{[1
]}

Herdman, Laura ^{[1
]}

Coutinho, Patricia ^{[1
]}

Fagan, Harry ^{[1
]}

Antonopoulos, Alexios S. ^{[1
]}

Oikonomou, Evangelos K. ^{[1
]}

Thomas, Sheena ^{[1
]}

Chiu, Amy P. ^{[1
]}

Chuaiphichai, Surawee ^{[1
]}

Kotanidis, Christos P. ^{[1
]}

Christodoulides, Constantinos ^{[2
]}

Petrou, Mario ^{[3
]}

Krasopoulos, George ^{[3
]}

Sayeed, Rana ^{[3
]}

Lv, Lei ^{[1
]}

Hale, Ashley ^{[1
]}

Kararoudi, Meisam Naeimi ^{[1
]}

McNeill, Eileen ^{[1
]}

Douglas, Gillian ^{[1
]}

George, Sarah ^{[4
]}

Tousoulis, Dimitris ^{[5
]}

Channon, Keith M. ^{[1
]}

Antoniades, Charalambos ^{[1
]}

机构：

[1] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford OX3 9DU, England

[2] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LE, England

[3] Oxford Univ Hosp NHS Trust, Dept Cardiothorac Surg, Oxford OX3 9DU, England

[4] Univ Bristol, Bristol Med Sch, Bristol Royal Infirm, Res Floor Level 7, Bristol BS2 8HW, Avon, England

[5] Athens Univ, Med Sch, Cardiol Dept, Athens 11527, Greece

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2019年 / 11卷 / 510期

基金：

英国惠康基金; 英国工程与自然科学研究理事会;

关键词：

SMOOTH-MUSCLE-CELLS; NITRIC-OXIDE; OXIDATIVE STRESS; CARDIOVASCULAR-DISEASE; HUMAN ATHEROSCLEROSIS; ENDOTHELIAL FUNCTION; INSULIN-RESISTANCE; QUANTIFICATION; ADIPONECTIN; DYSFUNCTION;

D O I：

10.1126/scitranslmed.aav5055

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页数：16

共 47 条

[1]

Blocking Wnt5a signaling decreases CD36 expression and foam cell formation in atherosclerosis [J].