Deleterious role of endothelial lectin-like oxidized low-density lipoprotein receptor-1 in ischaemia/reperfusion cerebral injury. Issue 11 (November 2019)

• Record Type: Journal Article
• Authors: Akhmedov, Alexander; Bonetti, Nicole R; Reiner, Martin F; Spescha, Remo D; Amstalden, Heidi; Merlini, Mario; Gaul, Daniel S; Diaz-Cañestro, Candela; Briand-Schumacher, Sylvie; Spescha, Rebecca S; Semerano, Aurora; Giacalone, Giacomo; Savarese, Gianluigi; Montecucco, Fabrizio; Kulic, Luka; Nitsch, Roger M; Matter, Christian M; Kullak-Ublick, Gerd A; Sessa, Maria; Lüscher, Thomas F; Beer, Jürg H; Liberale, Luca; Camici, Giovanni G
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 39:Issue 11(2019)
• Page Start: 2233
• Page End: 2245
• Publication Date: 2019-11
• Subjects: Cell death -- ischaemia/reperfusion -- lectin-like oxidized low-density lipoprotein receptor-1 -- middle cerebral artery occlusion -- stroke; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1177/0271678X18793266
• Languages: English
• ISSNs: 0271-678X

Abstract

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is implicated in cardiovascular disease by modulating apoptosis and oxidative stress. We hypothesized that LOX-1 may be involved in pathophysiology of stroke by mediating ischaemia/reperfusion (I/R)-dependent cell death. Transient middle cerebral artery occlusion (tMCAO) was performed in wild-type (WT) mice, endothelial-specific LOX-1 transgenic mice (eLOX-1TG) and WT animals treated with LOX-1 silencing RNA (siRNA). In WT mice exposed to tMCAO, LOX-1 expression and function were increased in the MCA. Compared to WT animals, eLOX-1TG mice displayed increased stroke volumes and worsened outcome after I/R. Conversely, LOX-1-silencing decreased both stroke volume and neurological impairment. Similarly, in HBMVECs, hypoxia/reoxygenation increased LOX-1 expression, while LOX-1 overexpressing cells showed increased death following hypoxia reoxygenation. Increased caspase-3 activation was observed following LOX-1 overexpression both in vivo and in vitro, thus representing a likely mediator. Finally, monocytes from ischaemic stroke patients exhibited increased LOX-1 expression which also correlated with disease severity. Our data unequivocally demonstrate a key role for LOX-1 in determining outcome following I/R brain damage. Our findings could be corroborated in human brain endothelial cells and monocytes from patients, underscoring their translational relevance and suggesting siRNA-mediated LOX-1 knockdown as a novel therapeutic strategy for stroke patients.