Deleterious role of endothelial lectin-like oxidized low-density lipoprotein receptor-1 in ischaemia/reperfusion cerebral injury: Journal of Cerebral Blood Flow and Metabolism

A Akhmedov, NR Bonetti, MF Reiner, RD Spescha, H Amstalden, M Merlini, DS Gaul, C Diaz-Cañestro, RS Spescha, A Semerano, G Giacalone, G Savarese, F Montecucco, L Kulic, RM Nitsch, CM Matter, GA Kullak-Ublick, M Sessa, TF Lüscher, JH BeerL Liberale, GG Camici

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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. © The Author(s) 2018.
Original languageEnglish
Pages (from-to)2233-2245
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Volume39
Issue number11
DOIs
Publication statusPublished - 2019

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Akhmedov, A., Bonetti, NR., Reiner, MF., Spescha, RD., Amstalden, H., Merlini, M., Gaul, DS., Diaz-Cañestro, C., Spescha, RS., Semerano, A., Giacalone, G., Savarese, G., Montecucco, F., Kulic, L., Nitsch, RM., Matter, CM., Kullak-Ublick, GA., Sessa, M., Lüscher, TF., ... Camici, GG. (2019). Deleterious role of endothelial lectin-like oxidized low-density lipoprotein receptor-1 in ischaemia/reperfusion cerebral injury: Journal of Cerebral Blood Flow and Metabolism. Journal of Cerebral Blood Flow and Metabolism, 39(11), 2233-2245. https://doi.org/10.1177/0271678X18793266