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  • Based upon these findings the S lipoxygenase

    2023-01-24

    Based upon these findings, the 12S-lipoxygenase seems to increase membrane excitability by specifically inhibiting M-type K+ channels. The 12S-lipoxygenase is expressed in many parts of mammalian CHIR-258 including the cerebrum, cerebellum, hypothalamus, basal ganglia, hippocampus, olfactory bulb, and pons [98]. A molecular correlation of KCNQ2 and KCNQ3 heteromultimeric K+ channels with M-channels has recently been reported [99], and the distribution of the M-type channels appears to overlap partially with that of the 12S-lipoxygenase. Mutations leading to a partial loss of channel function in KCNQ2 and KCNQ3 were found in newborns with inherited epilepsy [100]. In addition, kainic acid-induced seizures in rats were reduced by inhibiting the lipoxygenase [101], [102]. Therefore, 12S-lipoxygenase could be a clinical target for the prevention and treatment of epilepsy by inhibition of M-type K+ channels. There is a report suggesting that the formation of 12-lipoxygenase metabolites is important for hippocampal homosynaptic long-term depression [103], although the study was carried out using non-specific lipoxygenase inhibitors together with cyclooxygenase inhibitors. Moreover, the 12-lipoxygenase is shown to modulate glutamate release in hippocampal mossy fiber terminals [104], [105]. These results suggest a role for 12-lipoxygenase in the release of neurotransmitters, although further investigations are necessary to establish this point.
    Clinical disorders and enzyme abnormality There have been reports of platelet 12-lipoxygenase deficiencies in myeloproliferative disorders [106], [107], [108]. Patients with deficient lipoxygenase activities tend to have episodes of hemorrhage rather than thrombosis, and bleeding complications occurred in 67% of these patients [106]. Three patients with decreased levels of 12-lipoxygenase mRNA and protein have been reported [107], and a patient with essential thrombocythemia had a deficiency of 12-lipoxygenase activity, but normal amounts of enzyme protein were found [108]. An increased platelet sensitivity to ADP was observed in mice lacking platelet-type 12S-lipoxygenase, suggesting that a product of this enzyme suppresses platelet activation by ADP [109]. Several lines of evidence support the hypothesis that oxidized LDL contributes to atherogenesis and that the lipoxygenase participates in this oxidative process [6], [7], [8]. As described above, the leukocyte-type 12S-lipoxygenases of many species seem to be the equivalent of human and rabbit 15-lipoxygenases (Table 1). These enzymes have been referred to as 12/15-lipoxygenases, and have the ability to directly oxygenate unsaturated fatty acids contained in LDL. Enhanced oxidation of LDL by zymosan-stimulated macrophages is suppressed in the leukocyte-type 12S-lipoxygenase-deficient macrophages [22]. Moreover, disruption of the leukocyte-type 12S-lipoxygenase gene diminishes atherosclerosis in atherosclerosis-prone apo E-deficient mice [110]. However, a controversial result has come from studies of transgenic rabbits that express 15-lipoxygenase in a macrophage-specific manner [111]. In this model, 15-lipoxygenase overexpression in monocytes–macrophages protects against lipid deposition in the vessel wall during early atherogenesis. Although the 12/15-lipoxygenase of monocyte–macrophage appears to contribute to the cell-mediated LDL oxidation, a question arises as to whether the intracellular enzyme oxygenates LDL that is present in plasma. We demonstrated that the 12S-lipoxygenases overexpressed in mouse macrophage-like J774A.1 cells catalyzed the stereospecific oxygenation of esterified unsaturated fatty acid in LDL [112]. As for the mechanisms of the cell-mediated LDL oxidation, a possibility of secretion or leakage of the enzyme was ruled out, because no enzymatic activity was detected in the culture medium. We assume that some membrane receptor that binds LDL is involved in this oxidation process. Possible receptors are LDL receptor, LDL receptor-related protein (LRP) and scavenger receptor type BI all of which are expressed in cells of macrophage lineage as well as in atherosclerotic regions [113], [114]. Importantly, the LDL receptor is not required for cell-mediated LDL oxidation as shown by in vitro experiments [115] and LDL receptor-deficient mice studies [116], [117]. We have shown that LRP, but not the LDL receptor or scavenger receptor, was responsible for the 12/15-lipoxygenase-mediated LDL oxidation by the macrophage-like cells as well as by murine peritoneal macrophages [118]. It is suggested that HDL is a selective inhibitor of platelet 12S-lipoxygenase and plays a protective role in atherogenesis by preventing the generation of 12-HETE [119]. Therefore, the 12/15-lipoxygenase-LRP receptor system is a possible clinical target for the treatment and prevention of atherosclerosis.