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    • Several in vivo and in vitro studies have demonstrated chang

    2023-11-20

    Several in vivo and in vitro studies have demonstrated changes in bioactive lipid profiles under hyperglycemic conditions and have linked these changes with increased leukocyte adhesion and vascular dysfunction during diabetes. This input has originated partly from lipidomic studies that showed elevated levels of LO products including 5-, 12-, and 15-HETE released from aortic endothelial EZLink Sulfo-NHS-SS-Biotin Kit sale (AECs) and smooth muscle cells cultured under hyperglycemic conditions [34,35]. Enhanced expression of 12/15-LO and production of HETEs have also been reported in patients with diabetic vascular complications [20,36], in vessels from infants of diabetic mothers [37], and in experimental animal models of diabetes [38,39]. These findings have been extended by Patriacia et al. study, where 12- and 15-HETEs per se induced a similar increase in monocyte adhesion to human AECs as seen with glucose alone [34]. Furthermore, the specific role of 12-LO in glucose-induced monocyte-endothelial interactions was reinforced by additional studies showing a marked inhibition of high glucose-stimulated monocyte adhesion in AECs treated with a catalytically active ribozyme directed against 12-LO [40]. In support of the relevance of this pathway in vivo, inhibition of 12/15-LO in isolated primary AECs from db/db mice reduced the monocyte adhesion to db/db endothelium [38]. All of these reports strengthen the concept that modulation of the 12/15-LO pathway in endothelial cells may provide a therapeutic benefit for early vascular inflammation in diabetes. Consistent with these previous studies, we and others [41] have observed a similar pro-inflammatory phenotype, characterized by increased ICAM-1 expression and monocyte adhesion, in human retinal endothelial cells (HRECs) under hyperglycemic conditions. However, this study is the first to show that glucose regulates the acquisition of this phenotype in retinal endothelial cells through 12/15-LO. Furthermore, our study suggests that endothelial 12/15-LO rather than the monocytic/macrophagic 12/15-LO plays an important role in this process. Evidence for such differential activity of systemic and retinal 12/15-LO during diabetes was inferred from our in vivo and in vitro studies. In our in vivo study, there were no significant changes in the plasma levels of major metabolites derived from 12/15-lipoxygenation of different PUFAs, including LA (13-HODE), AA (12- and 15- HETEs), EPA (12- and 15- HEPEs), or DHA (17-HDoHE). In addition, there were no significant changes in the plasma levels of other metabolites derived from 12/15-lipoxygenase, including LXA4, LXB4, 5,15-DiHETE, 8,15-DiHETE (Table 1). Of note, the only increased metabolite in the plasma of diabetic mice among those derived from 15-LO pathway was RvD2 (7S,16R,17S-trihydroxy-DHA) and this point needs further discussion because RvD2 is formed by multiple enzymes including 15-LO. It is formed by the initial metabolism of DHA to 17S-hydroxy-DHA by 15-LO followed by further metabolism by 5-LO to 7S-hydroxy-derivative and then by Cytochrome P450 monooxygenase to 7(S),16(R),17(S)-Resolvin D2 [42]. The observations that the level of the intermediate (17-HDoHE), which is derived from 15-LO, did not change in diabetes together with increased levels of CYP/sEH products, may provide clues that the alteration in RvD2 level observed is most likely due to the increased enzymatic activity of the subsequent metabolic pathways rather than the initial metabolism by 15-LO. These in vivo results were further corroborated by our in vivo data that showed that leukocytes from 12/15-LO−/− mice displayed a similar increase in adhesion to activated endothelial cells as did leukocytes from WT mice. However, because systemic and local bioactive metabolite changes might be very different, it does not necessarily mean that the local change is the only driving force for leukocyte adhesion in DR. Another important finding of our study is the observation that high glucose per se does not affect TER in mature HREC monolayers; but at the same time it does upregulate ICAM-1 directly and activates HRECs to leukocyte adhesion. This would imply that high glucose affects TER in mature HREC monolayers indirectly through activation of HRECs to leukocyte adhesion. This explains what we have seen in Fig. 4; no drop in TER with direct HG-treatment compared to LG-treatment until monocytes were added.