Biosynthetic Crossover of 5-Lipoxygenase and Cyclooxygenase-2 Yields 5-Hydroxy-PGE2 and 5-Hydroxy-PGD2

Nakashima, Fumie; Suzuki, Takashi; Gordon, Odaine N.; Golding, Dominic; Okuno, Toshiaki; Giménez‐Bastida, Juan Antonio; Yokomizo, Takehiko; Schneider, Claus M.

doi:10.26434/chemrxiv.14376866

Cited by 2 publications

(1 citation statement)

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“…Following the initial oxidation of arachidonic acid by 5-lipoxygenase (5-LOX) or cyclooxygenase-2 (COX-2), respectively, the biosynthetic reactions proceed along separate pathways (1-3). Arachidonic acid can also undergo consecutive oxygenation by 5-LOX and COX-2 to yield two hemiketal (HK) eicosanoids, HKE 2 and HKD 2 (4) as well as the 5-hydroxyprostaglandins, 5-OH-PGE 2 and 5-OH-PGD 2 (5). The cross-over biosynthetic pathway entails initial oxygenation of arachidonic acid by 5-LOX to form 5 S -HETE that subsequently undergoes oxygenation by COX-2.…”

Section: Introductionmentioning

confidence: 99%

The 5-LOX/COX-2 cross-over metabolite, hemiketal E₂, enhances VEGFR2 activation and promotes angiogenesis

Nakashima¹,

Giménez‐Bastida²,

Luis³

et al. 2022

Preprint

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Consecutive oxygenation of arachidonic acid by 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) yields the hemiketal (HK) eicosanoids, HKE2 and HKD2. HKs stimulate angiogenesis by inducing endothelial cell tubulogenesis in culture; however, how this process is regulated has not been determined. Here, we identify vascular endothelial growth factor receptor 2 (VEGFR2) as a mediator of HKE2-induced angiogenesis in vitro and in vivo. HKE2 treatment of human umbilical vein endothelial cells dose-dependently increased phosphorylation of VEGFR2 and the downstream kinases ERK and Akt that mediated endothelial cell tubulogenesis. In vivo, HKE2 induced the growth of blood vessels into polyacetal sponges implanted in mice. HKE2-mediated effects in vitro and in vivo were blocked by the VEGFR2 inhibitor vatalanib, indicating that the pro-angiogenic effect of HKE2 was mediated by VEGFR2. We found that HKE2 covalently bound and inhibited PTP1B, a protein tyrosine phosphatase that dephosphorylates VEGFR2, thereby providing a possible molecular mechanism for how HKE2 induced pro-angiogenic signaling. Our studies indicate that biosynthetic cross-over of the 5-LOX and COX-2 pathways gives rise to a potent lipid autacoid that regulates endothelial cell function in vitro and in vivo.SignificanceAngiogenesis, the growth of new blood vessels from existing vessels, contributes to both physiological and pathological conditions, including tissue repair after injury and tumorigenesis. Novel approaches to control pathologic angiogenesis are urgently needed since current therapy targeting the pro-angiogenic receptor VEGFR2 has significant side effects. We show that a metabolite of arachidonic acid, formed in a biosynthetic cross-over of the enzymes that generate the pro-inflammatory leukotriene and prostaglandin mediators, respectively, promotes VEGFR2 activation to induce angiogenesis. This finding suggests that common drugs targeting the arachidonic acid pathway may be viewed as valid anti-angiogenic candidates.

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Section: Introductionmentioning

confidence: 99%

The 5-LOX/COX-2 cross-over metabolite, hemiketal E₂, enhances VEGFR2 activation and promotes angiogenesis

Nakashima¹,

Giménez‐Bastida²,

Luis³

et al. 2022

Preprint

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Targeting Mammalian 5-Lipoxygenase by Dietary Phenolics as an Anti-Inflammatory Mechanism: A Systematic Review

Giménez‐Bastida

González‐Sarrías

Llopis

et al. 2021

IJMS

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5-Lipoxygenase (5-LOX) plays a key role in inflammation through the biosynthesis of leukotrienes and other lipid mediators. Current evidence suggests that dietary (poly)phenols exert a beneficial impact on human health through anti-inflammatory activities. Their mechanisms of action have mostly been associated with the modulation of pro-inflammatory cytokines (TNF-α, IL-1β), prostaglandins (PGE2), and the interaction with NF-κB and cyclooxygenase 2 (COX-2) pathways. Much less is known about the 5-lipoxygenase (5-LOX) pathway as a target of dietary (poly)phenols. This systematic review aimed to summarize how dietary (poly)phenols target the 5-LOX pathway in preclinical and human studies. The number of studies identified is low (5, 24, and 127 human, animal, and cellular studies, respectively) compared to the thousands of studies focusing on the COX-2 pathway. Some (poly)phenolics such as caffeic acid, hydroxytyrosol, resveratrol, curcumin, nordihydroguaiaretic acid (NDGA), and quercetin have been reported to reduce the formation of 5-LOX eicosanoids in vitro. However, the in vivo evidence is inconclusive because of the low number of studies and the difficulty of attributing effects to (poly)phenols. Therefore, increasing the number of studies targeting the 5-LOX pathway would largely expand our knowledge on the anti-inflammatory mechanisms of (poly)phenols.

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Biosynthetic Crossover of 5-Lipoxygenase and Cyclooxygenase-2 Yields 5-Hydroxy-PGE2 and 5-Hydroxy-PGD2

Cited by 2 publications

References 10 publications

The 5-LOX/COX-2 cross-over metabolite, hemiketal E₂, enhances VEGFR2 activation and promotes angiogenesis

The 5-LOX/COX-2 cross-over metabolite, hemiketal E₂, enhances VEGFR2 activation and promotes angiogenesis

Targeting Mammalian 5-Lipoxygenase by Dietary Phenolics as an Anti-Inflammatory Mechanism: A Systematic Review

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Biosynthetic Crossover of 5-Lipoxygenase and Cyclooxygenase-2 Yields 5-Hydroxy-PGE2 and 5-Hydroxy-PGD2

Cited by 2 publications

References 10 publications

The 5-LOX/COX-2 cross-over metabolite, hemiketal E2, enhances VEGFR2 activation and promotes angiogenesis

The 5-LOX/COX-2 cross-over metabolite, hemiketal E2, enhances VEGFR2 activation and promotes angiogenesis

Targeting Mammalian 5-Lipoxygenase by Dietary Phenolics as an Anti-Inflammatory Mechanism: A Systematic Review

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The 5-LOX/COX-2 cross-over metabolite, hemiketal E₂, enhances VEGFR2 activation and promotes angiogenesis

The 5-LOX/COX-2 cross-over metabolite, hemiketal E₂, enhances VEGFR2 activation and promotes angiogenesis