The Arachidonate 15-Lipoxygenase Enzyme Product 15-HETE Is Present in Heart Tissue from Patients with Ischemic Heart Disease and Enhances Clot Formation

Abstract

Ischemic heart disease is a major cause of death and morbidity and the search for novel therapeutic targets is still required. We have previously shown that the enzyme arachidonate 15 lipoxygenase (ALOX15), which catalyzes the conversion of arachidonic acid to 15-hydroxy eicosatetraenoic acid (15-HETE), is highly expressed in ischemic heart tissue, but its role in the pathogenesis of ischemic heart disease is unclear. Here we showed that expression of ALOX15, but not ALOX12 or ALOX15B, was increased in ischemic versus non-ischemic human heart biopsy samples. A similar ALOX expression pattern was found in hypoxic human cardiomyocytes and cardiac endothelial cells. We also showed that levels of 15-HETE were significantly higher in ischemic versus non-ischemic human heart biopsy samples and showed a tendency to increase in serum from the patients with ischemic heart disease. Moreover, hypoxia increased the production of 15-HETE levels from human cardiomyocytes and cardiac endothelial cells. The hypoxia-induced increase in 15-HETE levels from human cardiomyocytes was inhibited by the ALOX15 inhibitor baicalein. Finally, by using intrinsic rotational thromboelastometry, we showed that human whole blood clotted faster in the presence of 15-HETE. In summary, we propose that increased ALOX15 expression in heart tissue under ischemic conditions may lead to increased production of 15-HETE, potentially contributing to thrombosis.

Replacement of an Indole Scaffold Targeting Human 15‐Lipoxygenase‐1 Using Combinatorial Chemistry

“…[6,7] (15S)-HETE is reported to be present in the heart tissue of patients with ischemic heart disease and it contributes to accelerated clot formation. [8] Also an increase of 12/15-LOX levels in the peri-infarct cortex of two stroke patients has been reported, suggesting their important role in human stroke. [9] Another metabolite from the linoleic acid metabolism pathway is (13S)-HODE, which has been shown to induce airway epithelial injury leading to severe asthma.…”

Cancer Stem Cells: «Emergency Service» for Tumors Under Generalized Cellular Stress

“…Более поздние исследования показали, что гипоксия -необходимое условие существования нормальных плюри/мультипотентных стволовых клеток [33][34][35], а также индуцирует формирование стволового фенотипа в опухолевых клетках [36][37][38][39]. Анализ литературных данных показал, что 35 из 96 идентифицированных нами «генов стволовости» так или иначе активируются в условиях локальной или системной гипоксии: Abca1 [40], Acpp [41], Aldh1a1 [42], Alox15 [43], Amy1 [44], Arg2 [45], Blnk [46], Cacna1d [47], Ccr3 [48], Cd55 [49], Cldn1 [50], Cp [51], Fgfr1 [52,53], Gas6 [54], Gata6 [55], Gdf6 [56], Igf1 [57], Igf2 [58], Il10 [59], Lyve1 [60], Mmp2 [61], Nfatc2 [62], Nrcam [61], Nt5e [63], Nts [64], Pde4d [65], Pdk4 [66], Per2 [67], Pf4 [68], Prok2 [69], Pvrl1 [70], Slc2a4 [71], Slco4a1 [72], Trpv4 [73], Wnt5a [74].…”

Hypoxic cardiac fibroblasts from failing human hearts decrease cardiomyocyte beating frequency in an ALOX15 dependent manner

“…While ischemic heart disease and hypertension are known to be the major causes of heart failure, underlying pathogenic mechanisms must be further elucidated to develop novel treatments. Human lipoxygenases are a family of lipid-peroxidizing enzymes that have been implicated in pathogenesis of ischemic heart disease [ 1 , 2 ], heart failure [ 3 , 4 ] and stroke [ 5 , 6 ]. Arachidonate 15-lipoxygenase (ALOX15) catalyzes the conversion of arachidonic acid to 15-hydroxy eicosatetraenoic acid (15-HETE) [ 7 ].…”

“…The expression patterns of ALOX15 and ALOX15B in failing human hearts has however not been investigated previously. Hypoxic human cardiac endothelial cells, as well as cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs), have previously been shown to express ALOX15 and 15-HETE [ 2 ]. Activated cardiac fibroblasts have been implicated in cardiac dysfunction as inflammatory response mediators after myocardial infarction, and fibroblast inflammatory signaling has been shown to contribute to cardiac disease [ 11 , 12 ].…”