title: 12- and 15-lipoxygenases in human carotid atherosclerotic lesions: associations with cerebrovascular symptoms.
abstract: Lipoxygenase (ALOX) enzymes are implicated in both pro- and anti-atherogenic processes. The aim of this study was to investigate mRNA expression of 12- and 15-lipoxygenases (ALOX12, ALOX12B, ALOX15, ALOX15B) and the atypical ALOXE3 in human carotid atherosclerotic lesions, in relation to cerebrovascular symptoms and risk factors. The Biobank of Karolinska Endarterectomies (BiKE) collection of human carotid plaque tissue and associated clinical data was utilized (n=132). Lesion mRNA levels were analyzed by TaqMan qPCR (n=132) and microarray hybridization (n=77). Of the investigated mRNAs, only ALOX15B (15-LOX-2; epidermis-type 15-LOX) was readily detected in all plaque samples by qPCR, and thus suitable for quantitative statistical evaluation. ALOX12, ALOX12B, ALOX15 and ALOXE3 were detected with lower frequency and at lower levels, or virtually undetected. Microarray analysis confirmed ALOX15B as the most abundant 12- or 15-lipoxygenase mRNA in carotid lesions. Comparing plaques with or without attributable cerebrovascular symptoms (amaurosis fugax, transient ischemic attack, or stroke), ALOX15B mRNA levels were higher in symptomatic than asymptomatic plaques (1.31 [1.11-1.56], n=102; and 0.79 [0.55-1.15], n=30, respectively; p=0.008; mean [95% CI], arbitrary units). Multiple regression analysis confirmed symptomatic/asymptomatic status as a significant determinant of ALOX15B mRNA levels, independently of potentially confounding factors. Immunohistochemical analyses showed abundant ALOX15B expression in macrophage-rich areas of carotid lesions, and lipidomic analyses demonstrated the presence of typical ALOX15B products in plaque tissue. In summary, we observed associations between high ALOX15B expression in carotid lesions and a history of cerebrovascular symptoms. These findings suggest a link between ALOX15B and atherothrombotic events that merits further investigation.
authors.affiliation: Department of Medicine, Center for Molecular Medicine, Unit of Experimental Cardiovascular Research, Karolinska Institutet, Stockholm SE-17176, Sweden. karl.gertow@ki.se
authors.forename: Karl
authors.initials: K
authors.lastname: Gertow
authors.forename: Elena
authors.initials: E
authors.lastname: Nobili
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.forename: John W
authors.initials: JW
authors.lastname: Newman
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Pedersen
authors.forename: Johan
authors.initials: J
authors.lastname: Ekstrand
authors.forename: Jesper
authors.initials: J
authors.lastname: Swedenborg
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kühn
authors.forename: Craig E
authors.initials: CE
authors.lastname: Wheelock
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.forename: Ulf
authors.initials: U
authors.lastname: Hedin
authors.forename: Jesper Z
authors.initials: JZ
authors.lastname: Haeggström
authors.forename: Anders
authors.initials: A
authors.lastname: Gabrielsen
mesh_terms: D000368:Aged; D020757:Amaurosis Fugax / Q000209:etiology; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D050197:Atherosclerosis / Q000150:complications* / Q000201:enzymology; D016893:Carotid Stenosis / Q000201:enzymology*; D005260:Female; D006801:Humans; D002546:Ischemic Attack, Transient / Q000209:etiology; D008297:Male; D058226:Plaque, Atherosclerotic / Q000201:enzymology*; D012333:RNA, Messenger / Q000032:analysis; D020521:Stroke / Q000209:etiology
chemical_list: D012333:RNA, Messenger; D001092:Arachidonate 12-Lipoxygenase; C458528:ALOX15B protein, human; D001093:Arachidonate 15-Lipoxygenase