Elevated plasma WNT5A was independently associated with calcified coronary plaque progression and new-onset calcification, driven by USP17/RAC1-mediated activation of vascular NADPH oxidases.
Observational (n=1,004)
No
Is WNT5A associated with vascular oxidative stress and coronary plaque progression in obesity?
WNT5A acts as a mechanistic link between obesity and vascular disease pathogenesis by inducing arterial oxidative stress and coronary plaque progression.
Effect estimate: Bstand=0.242
p-value: p=0.047
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.
Akoumianakis et al. (Wed,) conducted a observational in Obesity and Coronary Artery Disease (n=1,004). Elevated plasma WNT5A vs. Lower plasma WNT5A / Non-CAD controls was evaluated on Progression of calcified coronary plaque (Bstand=0.242, p=0.047). Elevated plasma WNT5A was independently associated with calcified coronary plaque progression and new-onset calcification, driven by USP17/RAC1-mediated activation of vascular NADPH oxidases.