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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Class E Scavenger Receptors
Reperfusion Injury
Wild Animals
Middle Cerebral Artery Infarction
Stroke
RNA Interference
Stroke Volume
Transgenic Mice
Monocytes
Brain Ischemia
Caspase 3
Reperfusion
Oxidative Stress
Cell Death
Cardiovascular Diseases
Ischemia
Endothelial Cells
Apoptosis
Brain
Hypoxia

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

Deleterious role of endothelial lectin-like oxidized low-density lipoprotein receptor-1 in ischaemia/reperfusion cerebral injury. / Akhmedov, Alexander; Bonetti, Nicole R.; Reiner, Martin F.; Spescha, Remo D.; Amstalden, Heidi; Merlini, Mario; Gaul, Daniel S.; Diaz-Cañestro, Candela; 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.

In: Journal of Cerebral Blood Flow and Metabolism, 01.01.2018.

Research output: Contribution to journalArticle

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, Beer, JH, Liberale, L & Camici, GG 2018, '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
Akhmedov, Alexander ; Bonetti, Nicole R. ; Reiner, Martin F. ; Spescha, Remo D. ; Amstalden, Heidi ; Merlini, Mario ; Gaul, Daniel S. ; Diaz-Cañestro, Candela ; 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. / Deleterious role of endothelial lectin-like oxidized low-density lipoprotein receptor-1 in ischaemia/reperfusion cerebral injury. In: Journal of Cerebral Blood Flow and Metabolism. 2018.
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AU - Akhmedov, Alexander

AU - Bonetti, Nicole R.

AU - Reiner, Martin F.

AU - Spescha, Remo D.

AU - Amstalden, Heidi

AU - Merlini, Mario

AU - Gaul, Daniel S.

AU - Diaz-Cañestro, Candela

AU - Spescha, Rebecca S.

AU - Semerano, Aurora

AU - Giacalone, Giacomo

AU - Savarese, Gianluigi

AU - Montecucco, Fabrizio

AU - Kulic, Luka

AU - Nitsch, Roger M.

AU - Matter, Christian M.

AU - Kullak-Ublick, Gerd A.

AU - Sessa, Maria

AU - Lüscher, Thomas F.

AU - Beer, Jürg H.

AU - Liberale, Luca

AU - Camici, Giovanni G.

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N2 - 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.

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