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    • The surprising finding of our study is that human

    2022-11-09

    The surprising finding of our study is that human M1 macrophages stimulated by LPS express ALOX15B to high levels. So far 12/15-lipoxygenase activity was only reported for IL-4 stimulated anti-phlogistic M2 macrophages [9] but not for the classically activated M1 macrophages. Our data suggest that such M1 macrophages will specifically express ALOX15B while the M2 macrophages express both ALOX15 and ALO15B isoforms to similar levels. From an enzymatic point of view there are differences between the two 15-lipoxygenases considering substrate preference and positional specificity, which may even influence the role of the two iso-enzymes in atherosclerosis. In general, ALOX15B seems to preferentially oxygenate arachidonic AZD1152 receptor leading to the formation of the anti-inflammatory lipid mediators while it metabolizes linoleic acid to 13(S)-hydro(per)oxy-octadecadienoic acid (13-HpODE) involved in LDL-oxidation to a lesser extend than ALOX15 [24], [25]. In addition, ALOX15B was reported to be enzymatically active for longer periods, in contrast to ALOX15 for which rapid suicide inactivation has been observed [25], [26]. These substrate preferences and the lack of suicide inactivation may suggest an even more anti-inflammatory metabolite profile for human ALOX15B than for ALOX15. ALOX15 expression was co-localized with LDL to macrophage-rich areas in early atherosclerotic lesions in humans [27], [28], [29], [30] and specific ALOX15 products were observed in these lesions [29], [31]. However, conflicting results have been observed about the temporal and regiospecific expression patterns of the peroxidizing ALOX15 enzyme in humans. ALOX15 protein and mRNA were detected in macrophage-rich areas of human fatty streaks as well as in more advanced human atherosclerotic lesions by in situ hybridization [31]. The expression of ALOX15 in early atherosclerotic lesions was corroborated by measuring the specific ALOX15 metabolite 13-HpODE in arterial sections [29], [32]. This study showed that the specific ALOX15 metabolite was abundant in early human atherosclerotic lesions but was not in later stages of plaque development, where non-enzymatic lipid peroxidation surpassed the ALOX15 dependent lipid peroxidation [29], [32]. Therefore, ALOX15 may play a role in the initiation of atherosclerosis but not in later stages of atherogenesis. However, the expression of ALOX15 in early atherosclerotic development was later questioned by investigations which only detected minor human ALOX15 mRNA and protein in atherosclerotic lesions and found no co-localization of ALOX15 with macrophages [15], [33]. Instead, ALOX15B expression was detected in human carotid atherosclerotic plaques and immunohistochemical analysis showed abundant ALOX15B in macrophages-rich areas of carotid lesions [13], [14], [15]. In these studies hypoxia was shown to regulate ALOX15B mRNA expression through a HIF-1 alpha mediated mechanism [14]. Our findings corroborate the upregulation of ALOX15B by hypoxia and expand our knowledge on the regulation of ALOX15B in macrophages, showing that the enzyme is not only regulated by HIF-1 alpha but also by IL-4 and LPS. Hence, a larger set of macrophages will have 15-lipoxygenase activity from ALOX15B expression including certain sets of M1 and M2 macrophages. The preferential expression of ALOX15B in human macrophages may explain why human genetic studies investigating the association of ALOX15 with cardiovascular disease did not show consistent results. Two rare functional polymorphisms have been characterized in the ALOX15 gene, which leads to increased (c. −292C>T) [34] and reduced (T560M) [10] enzyme activity, respectively. While the activating c. −292C>T polymorphism showed a trend towards an atheroprotective effect in a small case–control study for coronary artery disease, the inactivating T560M polymorphism was associated with a significantly increased risk for coronary artery disease in the ADVANCE study, indicating that ALOX15 may be anti-inflammatory and anti-atherogenic in humans [9], [10]. However, corroboration of such an atheroprotective effect of the ALOX15 gene failed in a larger case–control study on myocardial infarction possibly because of the low frequency of the T560M polymorphism [11]. So far all large Caucasian study samples investigating the association of the inactivating polymorphism (T560M) in ALOX15 showed a similar risk increase which was, however, not significant in two of the studies [10], [11]. In light of our results which emphasize that ALOX15B is the major 12/15-lipoxygenase in human macrophages, further research on the role of the ALOX15B gene in human atherosclerosis would be warranted.