The adipokine zinc-α2-glycoprotein predicts poor stroke outcome and impairs blood–brain barrier integrity
A Tirandi, L Liberale, S Ministrini, S Bengs, Y M Puspitasari, M Bertolotto, F Carbone, M Bacigaluppi, M Katan, F Montecucco, T F Luescher, G G CamiciAbstract
Introduction
Acute ischemic stroke (AIS) remains a major health challenge, underscoring the need for novel prognostic biomarkers and therapeutic targets. Zinc-α2-glycoprotein (ZAG) is an adipokine involved in metabolic regulation and inflammation and has recently gained attention in cardiovascular research. Despite the established contribution of inflammation to stroke pathophysiology, the role of ZAG in AIS has not yet been investigated. This study evaluated ZAG as a potential biomarker and mechanistic contributor to AIS.
Materials & Methods
ZAG was measured by ELISA in plasma of AIS patients from two independent cohorts. The first cohort included samples collected at 6 and 24 hours after onset of symptoms (n=22 and 15, respectively) and healthy controls (n=19). The second cohort included 283 AIS patients sampled within 24 hours of symptoms onset, in whom ZAG levels were correlated with 90-day functional outcomes. In parallel, in vitro studies were performed to assess the effects of ZAG on blood–brain barrier (BBB) integrity in primary human brain microvascular endothelial cells (HBMVECs) exposed to recombinant ZAG or PBS under normoxia or hypoxia–reoxygenation, with barrier function assessed via transendothelial electrical resistance.
Results
ZAG levels were decreased within the first 6h of AIS and returned toward control values by 24 hours (Figure 1A). Higher baseline ZAG levels within 24 hours of stroke onset were independently associated with unfavorable 90-day outcome (mRS 3–6; adjusted OR 1.07, 95% CI 1.02–1.13), after adjustment for age, sex, baseline NIHSS, and CRP (Figure 1B). In HBMVECs, recombinant ZAG induced a dose-dependent reduction in transendothelial barrier resistance, an effect further intensified by hypoxia–reoxygenation (Figure 2).
Conclusion
ZAG shows dynamic changes during the early phase of AIS, and elevated early circulating levels predict worse 90-day functional outcomes. In vitro, ZAG impairs BBB endothelial integrity suggesting a detrimental role of ZAG in stroke progression. Additional mechanistic studies are underway to further validate ZAG’s involvement in AIS pathophysiology.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.