Deleterious role of endothelial lectin-like oxidized low-density lipoprotein receptor-1 in ischaemia/reperfusion cerebral injury

Alexander Akhmedov, Nicole R. Bonetti, Martin F. Reiner, Remo D. Spescha, Heidi Amstalden, Mario Merlini, Daniel S. Gaul, Candela Diaz-Cañestro, Rebecca S. Spescha, Aurora Semerano, Giacomo Giacalone, Gianluigi Savarese, Fabrizio Montecucco, Luka Kulic, Roger M. Nitsch, Christian M. Matter, Gerd A. Kullak-Ublick, Maria Sessa, Thomas F. Lüscher, Jürg H. BeerLuca Liberale, Giovanni G. Camici

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalJournal of Cerebral Blood Flow and Metabolism
DOIs
Publication statusAccepted/In press - Jan 1 2018

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Keywords

  • Cell death
  • ischaemia/reperfusion
  • lectin-like oxidized low-density lipoprotein receptor-1
  • middle cerebral artery occlusion
  • stroke

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Cite this

Akhmedov, A., Bonetti, N. R., Reiner, M. F., Spescha, R. D., Amstalden, H., Merlini, M., Gaul, D. S., Diaz-Cañestro, C., Spescha, R. S., Semerano, A., Giacalone, G., Savarese, G., Montecucco, F., Kulic, L., Nitsch, R. M., Matter, C. M., Kullak-Ublick, G. A., Sessa, M., Lüscher, T. F., ... Camici, G. G. (Accepted/In press). Deleterious role of endothelial lectin-like oxidized low-density lipoprotein receptor-1 in ischaemia/reperfusion cerebral injury. Journal of Cerebral Blood Flow and Metabolism. https://doi.org/10.1177/0271678X18793266