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  • In summary our data have shown that


    In summary, our data have shown that one mechanism by which glucose may mediate monocyte–endothelial cell interaction in the retinal endothelial cells is via the 12/15-LO pathway Furthermore, our current and previously published data [20,22] indicate a differential role of endothelial 12/15-LO versus the one in monocytic/macrophagic cells in mediating the inflammatory responses during DR. We, therefore, conclude that glucose promotes production of 12- or 15-HETE through retinal endothelial 12/15-LO rather than monocye/macrophage 12/15-LO, which results in autocrine activation of endothelial cells and induction of ICAM-1 on the surface of HRECs that would allow monocytes to firmly adhere to the endothelium (Fig. 6). Because the interaction between monocytes and the endothelium is a key early event in the development of DR, targeting this enzyme in endothelial cells may facilitate the development of more precisely targeted treatment strategies for DR.
    Transparency document
    Acknowledgments This work has been supported by the National Eye Institute (NIH) Grant 5R01EY023315-02 (MA). This study was also supported in part by National Center for Research Resources Grant S10RR027926 for the lipid analysis and by James and Jean Culver Vision Discovery Institute (ASI). The work in NS laboratory is supported in part by non-restricted funds from Research to Prevent Blindness Foundation, Retina Research Foundation, EY016665, EY022883, and EPA 83573701. The authors would like to thank Dr. Bhagelu Achyut for his assistance with heat map making software.
    Introduction Lipoxygenases (LOs) catalyze the oxidation of free and esterified phospholipid fatty acids generating bioactive lipid mediators and reactive oxygen species (ROS) [13], [42]. The leukocyte-type 12/15 LO (L-12/15 LO) is expressed throughout Amyloid β-peptide (10-35), amide parenchyma in both neurons and glial cells of the cerebral cortex, basal ganglia, and hippocampus [33]. Physiologically, L-12/15 LO metabolites modulate several neuronal ion channel conductances [9], [29], [35], [47]. Pathophysiologically, L-12/15 LO activation is linked to neuronal cell death in animal models of both cerebral ischemia and Alzheimer’s disease [13], [22], [37], [46], [51] and in various in vitro models of oxidative stress [22], [26], [27], [32], [38], [54]. Although the exact mechanism(s) by which L-12/15 LO facilitates neuronal injury remain(s) to be fully elucidated, it is known to oxidatively modify lipoproteins and phospholipids [24], [44], [53] and to damage mitochondria [45]. Mitochondrial dysfunction is considered to be a common mediator of many acute and chronic neurological diseases, though it most closely and directly links to the pathophysiology of Huntington’s disease (HD), an adult-onset autosomal-dominant inherited neurodegenerative disease caused by a mutation in the short arm of human chromosome 4p16.3 [14], [28], [30]. Whether L-12/15 LO activation contributes to striatal damage in HD models has yet to be explored. 3-nitropropionic acid (3-NP)―a phyto/fungal toxin—irreversibly inhibits the electron transport enzyme succinate dehydrogenase (SDH) and produces striatal lesions and cognitive and motor dysfunction in rodents and primates that closely resemble that of human HD [5], [7], [34]. Thus, it was used herein to compare histological and behavioral outcomes of mice wild-type or null for alox15, the gene that encodes for the protein L-12/15 LO.
    Materials and methods
    Results Alox15+/+ and Alox15−/− were used to examine how loss of function of L-12/15 LO would affect 3-NP-induced motor system impairment and striatal toxicity. After the first four injections of 3-NP, mice did not display any visible neurological deficit symptoms (Fig. 1). Motor symptoms increased progressively thereafter in both genotypes similarly with increased days of dosing with 3-NP (Fig. 1A, p<0.0001 for day and p=0.827 for genotype) as did the expected reduction in gross body weight (Fig. 1B, p<0.0001 for day and p=0.469 for genotype). Despite this, not all mice, regardless of genotype, developed histologically-identifiable lesions (Fig. 2). However, the incidence of lesions between genotypes did differ (Fig. 2B). Only 19% of Alox15+/+ mice showed 3-NP induced striatal neurodegeneration, whereas the incidence of lesions in Alox15 −/− mice more than doubled to 43% (Fig. 2B, p=0.031). This increase was dominated by a high proportion of smaller lesions with a mean size of 20±4% of the total striatal area (Fig. 2B, p=0.006). Coincident with this was a genotype-dependent increase in morbundity with 44.4% of the Alox15−/− attaining a score of ≥9 compared to just 24.2% of Alox15+/+ littermate controls (Fig. 3A, p=0.039). However, the rate at which the mice in each genotypic group were removed—graphed as % survival—did not differ (Fig. 3B, p=0.086). To rule out the possibility that this underlying sensitivity to 3-NP was due to genotypic differences in striatal SDH inhibition, we quantified striatal SDH activity after an acute systemic injection of 3-NP (200mg/kg, i.p.). SDH activity in Alox15+/+ and Alox15−/− was reduced equally (64.4% vs 66.4%, respectively) (Fig. 4).