The 650-kDa 12(S)-Hydroxyeicosatetraenoic Acid Binding Complex: Occurrence in Human Platelets, Identification of Hsp90 as a Constituent, and Binding Properties of Its 50-kDa Subunit

Herbertsson, Helena; Kühme, Tobias; Hammarström, Sven

doi:10.1006/abbi.1999.1233

Cited by 16 publications

(8 citation statements)

References 26 publications

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“…Furthermore, whether 15-HETE can activate the same receptor as does 12-HETE has yet to be clarified. Others have demonstrated the ability of 12/15-LO products to bind an intracellular receptor that associates with other proteins, which is more reminiscent of nuclear receptor signaling [49, 50]. Such observations leave an open question with regard to 12/15-LO products: whether their cellular effects are mediated by a secreted product binding to a receptor or whether they act as second messengers within the cell.…”

Section: Discussionmentioning

confidence: 99%

Targeting of 12/15-Lipoxygenase in retinal endothelial cells, but not in monocytes/macrophages, attenuates high glucose-induced retinal leukostasis

Ibrahim

Saleh

El-Shafey

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Aims Our previous studies have established a role for 12/15-lipoxygenase (LO) in mediating the inflammatory response in diabetic retinopathy (DR). However, the extent at which the local or systemic induction of 12/15-LO activity involved is unclear. Thus, the current study aimed to characterize the relative contribution of retinal endothelial versus monocytic/macrophagic 12/15-LO to inflammatory responses in DR. Materials & Methods We first generated a clustered heat map for circulating bioactive lipid metabolites in the plasma of streptozotocin (STZ)-induced diabetic mice using liquid chromatography coupled with mass-spectrometry (LC-MS) to evaluate changes in circulating 12/15-LO activity. This was followed by comparing the in vitro mouse endothelium-leukocytes interaction between leukocytes isolated from 12/15-LO knockout (KO) versus those isolated from wild type (WT) mice using the myeloperoxidase (MPO) assay. Finally, we examined the effects of knocking down or inhibiting endothelial 12/15-LO on diabetes-induced endothelial cell activation and ICAM-1 expression. Results Analysis of plasma bioactive lipids’ heat map revealed that the activity of circulating 12/15-LO was not altered by diabetes as evident by no significant changes in the plasma levels of major metabolites derived from 12/15-lipoxygenation of different PUFAs, including linoleic acid (13-HODE), arachidonic acid (12- and 15- HETEs), eicosapentaenoic acid (12- and 15- HEPEs), or docosahexaenoic acid (17-HDoHE). Moreover, leukocytes from 12/15-LO KO mice displayed a similar increase in adhesion to high glucose (HG)-activated endothelial cells as do leukocytes from WT mice. Furthermore, abundant proteins of 12-LO and 15-LO were detected in human retinal endothelial cells (HRECs), while it was undetected (15-LO) or hardly detectable (12-LO) in human monocyte-like U937 cells. Inhibition or knock down of endothelial 12/15-LO in HRECs blocked HG-induced expression of ICAM-1, a well-known identified important molecule for leukocyte adhesion in DR. Conclusion Our data support that endothelial, rather than monocytic/macrophagic, 12/15-LO has a critical role in hyperglycemia-induced ICAM-1 expression, leukocyte adhesion, and subsequent local retinal barrier dysfunction. This may facilitate the development of more precisely targeted treatment strategies for DR.

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Section: Discussionmentioning

confidence: 99%

Targeting of 12/15-Lipoxygenase in retinal endothelial cells, but not in monocytes/macrophages, attenuates high glucose-induced retinal leukostasis

Ibrahim

Saleh

El-Shafey

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…These results indicate that 12(S)-HETE signaling through a PTx sensitive GPCR is only partially responsible for this increased VEGF presence and that other mechanisms of ERK1/2 stimulation are at work, such as 12(S)-HETE interaction with some intracellular, as yet uncharacterized, receptor of 12(S)-HETE. In fact 12(S)-HETE can bind to a 50-kDa protein [37] that exists as part of a high molecular weight cytosolic binding complex [38]; however, the functional implications of binding to this receptor remain to be determined. In addition, it is possible that 12(S)-HETE may promote VEGF transcription by binding to the nuclear receptor peroxisome proliferated activating receptor gamma (PPARg) [39], thus bypassing signaling through MAPKs completely.…”

Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor production in human prostate cancer cells is stimulated by overexpression of platelet 12-lipoxygenase

2006

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“…The latter high affinity binding sites (K d , 0.5 nM) were found to exist as a 50 kDa subunit within a 650 kDa cytosolic complex that also includes the heat shock proteins hsp70 and hsp90 and has been shown to occur in several cancer cell lines as well as in human platelets [94]. The 12S-HETE binding subunit dissociates from the complex in the presence of ATP and binds to NCOA1 (nuclear receptor coactivator-1) in the presence of 12S-HETE [125], suggesting that it may have a role in regulating gene transcription in the nucleus.…”

Section: Biological Actions Of Hetes and Oxoetesmentioning

confidence: 99%

Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid

Powell

Rokach

2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

263

206

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Arachidonic acid can be oxygenated by a variety of different enzymes, including lipoxygenases, cyclooxygenases, and cytochrome P450s, and can be converted to a complex mixture of oxygenated products as a result of lipid peroxidation. The initial products in these reactions are hydroperoxyeicosatetraenoic acids (HpETEs) and hydroxyeicosatetraenoic acids (HETEs). Oxoeicosatetraenoic acids (oxo-ETEs) can be formed by the actions of various dehydrogenases on HETEs or by dehydration of HpETEs. Although a large number of different HETEs and oxo-ETEs have been identified, this review will focus principally on 5-oxo-ETE, 5S-HETE, 12S-HETE, and 15S-HETE. Other related arachidonic acid metabolites will also be discussed in less detail. 5-Oxo-ETE is synthesized by oxidation of the 5-lipoxygenase product 5S-HETE by the selective enzyme, 5-hydroxyeicosanoid dehydrogenase. It actions are mediated by the selective OXE receptor, which is highly expressed on eosinophils, suggesting that it may be important in eosinophilic diseases such as asthma. 5-Oxo-ETE also appears to stimulate tumor cell proliferation and may also be involved in cancer. Highly selective and potent OXE receptor antagonists have recently become available and could help to clarify its pathophysiological role. The 12-lipoxygenase product 12S-HETE acts by the GPR31 receptor and promotes tumor cell proliferation and metastasis and could therefore be a promising target in cancer therapy. It may also be involved as a proinflammatory mediator in diabetes. In contrast, 15S-HETE may have a protective effect in cancer. In addition to GPCRs, higher concentration of HETEs and oxo-ETEs can activate peroxisome proliferator-activated receptors (PPARs) and could potentially regulate a variety of processes by this mechanism.

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The 650-kDa 12(S)-Hydroxyeicosatetraenoic Acid Binding Complex: Occurrence in Human Platelets, Identification of Hsp90 as a Constituent, and Binding Properties of Its 50-kDa Subunit

Cited by 16 publications

References 26 publications

Targeting of 12/15-Lipoxygenase in retinal endothelial cells, but not in monocytes/macrophages, attenuates high glucose-induced retinal leukostasis

Targeting of 12/15-Lipoxygenase in retinal endothelial cells, but not in monocytes/macrophages, attenuates high glucose-induced retinal leukostasis

Vascular endothelial growth factor production in human prostate cancer cells is stimulated by overexpression of platelet 12-lipoxygenase

Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid

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