Endothelial cyclooxygenase-1 paradoxically drives local vasoconstriction and atherogenesis despite underpinning prostacyclin generation

Mitchell, Jane A.; Shala, Fisnik; Pires, Maria Elisa Lopes; Loy, Rachel Y.; Ravendren, Andrew; Benson, Joshua; Urquhart, Paula; Nicolaou, Anna; Herschman, Harvey R.; Kirkby, Nicholas S.

doi:10.1126/sciadv.abf6054

Cited by 15 publications

(16 citation statements)

References 70 publications

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“…In a recently developed ecCOX1 − /− (endothelial specific knockout mouse for cyclooxygenase), EET production in whole aorta was not significantly altered but 15-HETE was reduced along with lower prostaglandin E2 and thromboxane. 25 Conversely, inhibition of lipoxygenase increases CYP-dependent EET level. 26 Inhibition of COX has been shown to shift AA into the lipoxygenase pool, which is the basis for COX-inhibitor induced exacerbation of respiratory disease.…”

Section: Discussionmentioning

confidence: 99%

Loss of Endothelial Cytochrome P450 Reductase Induces Vascular Dysfunction in Mice

et al. 2022

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BACKGROUND: POR (cytochrome P450 reductase) provides electrons for the catalytic activity of the CYP (cytochrome P450) monooxygenases. CYPs are dual-function enzymes as they generate protective vasoactive mediators derived from polyunsaturated fatty acids but also reactive oxygen species. It is not known in which conditions the endothelial POR/CYP system is beneficial versus deleterious. Here, the activity of all CYP enzymes was eliminated in the vascular endothelium to examine its impact on vascular function. METHODS: An endothelial-specific, tamoxifen-inducible POR knockout mouse (ecPOR − /− ) was generated. Vascular function was studied by organ chamber experiments. eNOS (endothelial nitric oxide synthase) activity was accessed by heavy arginine/citrulline LC-MS/MS detection and phosphorylation of serine1177 in aortic rings. CYP-derived epoxyeicosatrienoic acids and prostanoids were measured by LC-MS/MS. Gene expression of aorta and endothelial cells was profiled by RNA sequencing. Blood pressure was measured by telemetry. RESULTS: Acetylcholine-induced endothelium-dependent relaxation was attenuated in isolated vessels of ecPOR −/− as compared with control mice. Additionally, ecPOR −/− mice had attenuated eNOS activity and eNOS/AKT phosphorylation. POR deletion reduced endothelial stores of CYP-derived epoxyeicosatrienoic acids but increased vascular prostanoids. This phenomenon was paralleled by the induction of genes implicated in eicosanoid generation. In response to Ang II (angiotensin II) infusion, blood pressure increased significantly more in ecPOR − /− mice. Importantly, the cyclooxygenase inhibitor Naproxen selectively lowered the Ang II–induced hypertension in ecPOR − /− mice. CONCLUSIONS: POR expression in endothelial cells maintains eNOS activity and its loss results in an overactivation of the vasoconstrictor prostanoid system. Through these mechanisms, loss of endothelial POR induces vascular dysfunction and hypertension.

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Section: Discussionmentioning

confidence: 99%

Loss of Endothelial Cytochrome P450 Reductase Induces Vascular Dysfunction in Mice

et al. 2022

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“…This enzyme protects gastrointestinal mucosa, promotes platelet aggregation, and induces peripheral vascular resistance through regulation of prostacyclin synthesis, closely associated with thrombosis [ 45 – 47 ]. PTGS1 has clear vascular protective roles associated with the anti-thrombotic potential, vasoconstriction and the development of atherosclerosis and vascular inflammation [ 48 ]. On the other hand, the steroid hormone PGR, potentially reduces oxidative stress and neuroinflammation, regulates mitochondrial function, and promotes myelination by triggering several signaling pathways, such as the MAPK and NF-κ B signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology and in vitro studies reveal the pharmacological effects and molecular mechanisms of Shenzhi Jiannao prescription against vascular dementia

Tian

Gao

Chang

et al. 2022

BMC Complement Med Ther

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Background Shenzhi Jiannao (SZJN) prescription is a type of herbal formula adopted in the management of cognitive impairment and related disorders. However, its effects and related regulatory mechanisms on vascular dementia (VD) are elusive. Herein, network pharmacology prediction was employed to explore the pharmacological effects and molecular mechanisms of SZJN prescription on VD using network pharmacology prediction, and validated the results through in vitro experiments. Methods Through a search in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, chemical composition and targets for SZJN prescription were retrieved. The potential targets for VD were then obtained from the GeneCards and DisGeNET databases. The network was constructed that depicted the interactions between putative SZJN prescription and known therapeutic targets for VD using Cytoscape 3.7.1. Analysis of protein-protein interaction was achieved via STRING 11.0 software, followed by Gene Ontology (GO) functional enrichment and Kyoto Gene and Genome Encyclopedia (KEGG) pathway analyses. To validate the computer-predicted results, in vitro experiments based on an excitotoxic injury model were designed using glutamate-exposed PC12 cells, and treated with varying concentrations (low, 0.05; medium, 0.1 and high, 0.2 mg/mL) of SZJN prescription. Cell viability and cell death were detected using the IncuCyte imaging system. Moreover, the expression profiles of Caspase-3 were analyzed through qRT-PCR. Results Twenty-eight potentially active ingredients for SZJN prescription, including stigmasterol, beta-sitosterol, and kaempferol, plus 21 therapeutic targets for VD, including PTGS2, PTGS1, and PGR were revealed. The protein-protein interaction network was employed for the analysis of 20 target proteins, including CASP3, JUN, and AChE. The enrichment analysis demonstrated candidate targets of SZJN prescription were more frequently involved in neuroactive ligand-receptor interaction, calcium, apoptosis, and cholinergic synaptic signaling pathways. In vitro experiments revealed that SZJN prescription could significantly reverse glutamate-induced cell viability loss and cell death, and lower the levels of Caspase-3 mRNA in glutamate-induced PC12 cells. Conclusions Collectively, this study demonstrated that SZJN prescription exerted the effect of treating VD by regulating multi-targets and multi-channels with multi-components through the method of network pharmacology. Furthermore, in vitro results confirmed that SZJN prescription attenuated glutamate-induced neurotoxicity.

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“…This failure to realise the potential of targeting prostacyclin biology likely reflects the subsequent discovery of a great deal of complexity underlying its biology, including multiple synthetic pathways (McAdam et al, 1999), competing local and systemic actions (Kirkby et al, 2013b; and promiscuous receptor pharmacology (Liu et al, 2012a;Mitchell et al, 2021). Both difficulties of measuring prostacyclin synthesis in vivo (Mitchell et al, 2018) and side effects associated with systemic prostacyclin delivery also complicate exploiting prostacyclin biology for therapeutic purposes.…”

Section: Discussionmentioning

confidence: 99%

“…Thrombosis in vivo was measured using the mouse carotid artery ferric chloride injury model as we have previously described Mitchell et al, 2021). Briefly, under isoflurane anaesthesia the left carotid artery was exposed and separated from the attached nerve and vein.…”

Section: Thrombosismentioning

confidence: 99%

Tissue fibroblasts are a critical source of prostacyclin and anti-thrombotic protection

Mitchell

Vinokurova

Lopes-Pires

et al. 2022

Preprint

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Prostacyclin is an anti-thrombotic hormone long considered to be derived from the vascular endothelium. However, the role of non-vascular sources for prostacyclin synthesis has not been systematically evaluated due to a lack of tools. Here we used cell-specific knockout mice and human tissues to show that lung, and other tissues, are powerful producers of prostacyclin independent of their vascular components. Instead, in mice and humans, lung prostacyclin synthesis is associated with fibroblasts. The fibroblast-derived prostaglandins enter the circulation and provide systemic anti-thrombotic protection. These observations define a new paradigm in prostacyclin biology in which fibroblast/non-vascular-derived prostacyclin works in parallel with prostaglandins produced by the endothelium to control cardiovascular health. These results may explain how local diseases of the lung and elsewhere result in cardiovascular risk.

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Endothelial cyclooxygenase-1 paradoxically drives local vasoconstriction and atherogenesis despite underpinning prostacyclin generation

Cited by 15 publications

References 70 publications

Loss of Endothelial Cytochrome P450 Reductase Induces Vascular Dysfunction in Mice

Loss of Endothelial Cytochrome P450 Reductase Induces Vascular Dysfunction in Mice

Network pharmacology and in vitro studies reveal the pharmacological effects and molecular mechanisms of Shenzhi Jiannao prescription against vascular dementia

Tissue fibroblasts are a critical source of prostacyclin and anti-thrombotic protection

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