Molecular mechanisms and cell signaling of 20-hydroxyeicosatetraenoic acid in vascular pathophysiology

Fan, Fan; Ge, Ying; Lv, Wenshan; Elliott, Matthew R.; Muroya, Yoshikazu; Hirata, Takashi; Booz, George W.; Roman, Richard J.

doi:10.2741/4465

Cited by 78 publications

(21 citation statements)

References 353 publications

(380 reference statements)

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“…Moreover, Yamamoto et al also reported decreased arachidonic acid metabolism with the accumulation of COX-2, PGES, and the PGE receptor EP4 in renal tubules (12). In addition, several studies showed that 20-HETE, another important product of arachidonic acid metabolism, is elevated after IRI (13,14).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Molecular and Cellular Characterization of Acute Kidney Injury Progression to Renal Fibrosis

et al. 2021

Front. Immunol.

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Acute kidney injury (AKI) and chronic kidney disease (CKD) represent different stages of renal failure; thus, CKD can be regarded as a result of AKI deterioration. Previous studies have demonstrated that immune cell infiltration, oxidative stress, and metabolic mentalism can support renal fibrosis progression in AKI cases. However, the most important triggers and cell types involved in this pathological progression remain unclear. This study was conducted to shed light into the underlying cellular and molecular features of renal fibrosis progression through the analysis of three mouse whole kidney and one human single-cell RNA-sequencing datasets publicly available. According to the different causes of AKI (ischemia reperfusion injury [IRI] or cisplatin), the mouse samples were divided into the CIU [control-IRI-unilateral ureteral obstruction (UUO)] and CCU (control-cisplatin-UUO) groups. Comparisons between groups revealed eight different modules of differentially expressed genes (DEGs). A total of 1,214 genes showed the same expression pattern in both CIU and CCU groups; however, 1,816 and 1,308 genes were expressed specifically in the CCU and CIU groups, respectively. Further assessment of the DEGs according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway and Gene Ontology (GO) showed that T-cell activation, fatty acid metabolic process, and arachidonic acid metabolism were involved in the fibrosis progression in CIU and CCU. Single-cell RNA-sequencing data along with the collected DEGs information also revealed that the T-cell activation mainly happened in immune cells, whereas the fatty acid metabolic process and arachidonic acid metabolism occurred in tubule cells. Taken together, these findings suggest that the fibrosis process differed between the CIU and CCU stages, in which immune and tubule cells have different functions. These identified cellular and molecular features of the different stages of fibrosis progression may pave the way for exploring novel potential therapeutic strategies in the clinic.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Molecular and Cellular Characterization of Acute Kidney Injury Progression to Renal Fibrosis

et al. 2021

Front. Immunol.

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“…Therefore, therapy that targets the inhibition of ferroptosis may effectively prevent neuronal death, thereby reducing secondary brain injury after ICH (17). 20-Hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) plays an important role in regulating a wide variety of normal physiological functions as well as the pathogenesis of diverse disease conditions (18). This arachidonic acid metabolite synthesized by cytochrome P450 (CYP) 4A/F enzymes is increased in the plasma of patients with ischemic stroke and in cerebrospinal fluid of patients with aneurysmal subarachnoid hemorrhagic stroke (19,20).…”

Section: Introductionmentioning

confidence: 99%

20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis

et al. 2021

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Intracerebral hemorrhage (ICH) is a highly fatal type of stroke that leads to various types of neuronal death. Recently, ferroptosis, a form of cell death resulting from iron-dependent lipid peroxide accumulation, was observed in a mouse ICH model. N-hydroxy-N′-(4-n-butyl-2-methylphenyl)-formamidine (HET0016), which inhibits synthesis of the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE), has shown a protective effect after ICH. However, the underlying mechanisms of the neuroprotective effect need further investigation. We explored whether 20-HETE participates in ICH-induced ferroptosis ex vivo by using hemoglobin-treated organotypic hippocampal slice cultures (OHSCs) and in vivo by using a collagenase-induced ICH mouse model. Ex vivo, we found that the 20-HETE synthesis inhibitor HET0016 and antagonist 20-6,15-HEDGE reduced hemoglobin-induced cell death, iron deposition, and lipid reactive oxygen species levels in OHSCs. Furthermore, 20-HETE inhibition in OHSCs increased the expression of glutathione peroxidase (GPX) 4, an antioxidant enzyme that serves as a main regulator of ferroptosis. In contrast, exposure of OHSCs to the 20-HETE stable mimetic 20-5,14-HEDGE induced cell death that was significantly inhibited by the ferroptosis inhibitor ferrostatin-1. In vivo, HET0016 treatment ameliorated focal deficits, reduced lesion volume, and decreased iron accumulation around the lesion at day 3 and 7 after ICH. In addition, lipid peroxidation was decreased and expression of GPX4 was increased in the HET0016-treated ICH group. The mitogen-activated protein kinase pathway also was inhibited by HET0016 in vivo. These results indicate that 20-HETE contributes to ICH-induced acute brain injury in part by activating ferroptosis pathways, thereby providing an upstream target for inhibiting ferroptosis.

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“…Nevertheless, the K + perivascular concentration can determine switches between vasodilation and vasoconstriction [235,260,262,263]. The production of 20-hydroxyeicosatetraenoic acid downstream of the AA pathway in astrocytes has been related to the vasoconstriction of parenchymal brain vessels [258,[263][264][265][266]. These observations show the complex and regulated interactive signaling produced during the astrocytic Ca 2+ increase associated with the AA metabolism and K + released from astrocytes during NVC.…”

Section: Nvc Mediators In Astrocytes and Vascular Cellsmentioning

confidence: 93%

Connexin and Pannexin Large-Pore Channels in Microcirculation and Neurovascular Coupling Function

Burboa

Puebla

Gaete

et al. 2022

IJMS

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Microcirculation homeostasis depends on several channels permeable to ions and/or small molecules that facilitate the regulation of the vasomotor tone, hyperpermeability, the blood–brain barrier, and the neurovascular coupling function. Connexin (Cxs) and Pannexin (Panxs) large-pore channel proteins are implicated in several aspects of vascular physiology. The permeation of ions (i.e., Ca2+) and key metabolites (ATP, prostaglandins, D-serine, etc.) through Cxs (i.e., gap junction channels or hemichannels) and Panxs proteins plays a vital role in intercellular communication and maintaining vascular homeostasis. Therefore, dysregulation or genetic pathologies associated with these channels promote deleterious tissue consequences. This review provides an overview of current knowledge concerning the physiological role of these large-pore molecule channels in microcirculation (arterioles, capillaries, venules) and in the neurovascular coupling function.

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Molecular mechanisms and cell signaling of 20-hydroxyeicosatetraenoic acid in vascular pathophysiology

Cited by 78 publications

References 353 publications

Comprehensive Molecular and Cellular Characterization of Acute Kidney Injury Progression to Renal Fibrosis

Comprehensive Molecular and Cellular Characterization of Acute Kidney Injury Progression to Renal Fibrosis

20-HETE Participates in Intracerebral Hemorrhage-Induced Acute Injury by Promoting Cell Ferroptosis

Connexin and Pannexin Large-Pore Channels in Microcirculation and Neurovascular Coupling Function

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