Cyclooxygenase-2 Selectively Controls Renal Blood Flow Through a Novel PPARβ/δ-Dependent Vasodilator Pathway

Kirkby, Nicholas S.; Sampaio, Walkyria Oliveira; Etelvino, Gisele; Alves, Daniele T.; Anders, Katie L.; Temponi, Rafael; Shala, Fisnik; Nair, Anitha S.; Ahmetaj‐Shala, Blerina; Jiao, Jing; Herschman, Harvey R.; Wang, Xiaomeng; Wahli, Walter; Santos, Robson A.S.; Mitchell, Jane A.

doi:10.1161/hypertensionaha.117.09906

Cited by 34 publications

(24 citation statements)

References 41 publications

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“…Also, one of these reports further showed that the endothelial muscarinic agonist ACh evoked COX‐mediated contractile response, 50 similar to results obtained in renal arteries here or previously 22 . Moreover, there are reports including one on mice showing that PGI 2 or PGI 2 analogues evoke intrarenal vasoconstriction in vivo or ex vivo 21,51‐54 . These facts favor a general vasoconstrictor effect of PGI 2 via TP and EP3 on the mouse renal vasculature as suggested by findings of the present study.…”

Section: Discussionsupporting

confidence: 91%

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Differential properties of E prostanoid receptor‐3 and thromboxane prostanoid receptor in activation by prostacyclin to evoke vasoconstrictor response in the mouse renal vasculature

et al. 2020

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Vasomotor reactions of prostacyclin (prostaglandin I 2 ; PGI 2) can be collectively modulated by thromboxane prostanoid receptor (TP), E-prostanoid receptor-3 (EP3), and the vasodilator I prostanoid receptor (IP). This study aimed to determine the direct effect of PGI 2 on renal arteries and/or the whole renal vasculature and how each of these receptors is involved. Experiments were performed on vessels or perfused kidneys of wild-type mice and/or mice with deficiency in TP (TP −/−) and/ or EP3. Here we show that PGI 2 did not evoke relaxation, but instead resulted in contraction of main renal arteries (from ~0.001-0.01 µM) or reduction of flow in perfused kidneys (from ~1 µM); either of them was reversed into a dilator response in TP −/− /EP3 −/− counterparts. Also, we found that in renal arteries although it has a lesser effect than TP −/− on the maximal contraction to PGI 2 (10 µM), EP3 −/− but not TP −/− resulted in relaxation to the prostanoid at 0.01-1 µM. Meanwhile, TP −/− only significantly reduced the contractile activity evoked by PGI 2 at ≥0.1 µM. These results demonstrate that PGI 2 may evoke an overall vasoconstrictor response in the mouse renal vasculature, reflecting activities of TP and EP3 outweighing that of the vasodilator IP. Also, our results suggest that EP3, on which PGI 2 can have a potency similar to that on IP, plays a major role in the vasoconstrictor effect of the prostanoid of low concentrations (≤1 µM), while TP, on which PGI 2 has a lower potency but higher efficacy, accounts for a larger part of its maximal contractile activity.

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Section: Discussionsupporting

confidence: 91%

“…22 Moreover, there are reports including one on mice showing that PGI 2 or PGI 2 analogues evoke intrarenal vasoconstriction in vivo or ex vivo. 21,[51][52][53][54] These facts favor a general vasoconstrictor effect of PGI 2 via TP and EP3 on the mouse renal vasculature as suggested by findings of the present study.…”

Section: Discussionsupporting

confidence: 81%

Differential properties of E prostanoid receptor‐3 and thromboxane prostanoid receptor in activation by prostacyclin to evoke vasoconstrictor response in the mouse renal vasculature

et al. 2020

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“…Work from our group and of others has shown that activation of PPARβ can also explain some of the acute effects of prostacyclin in platelets and blood vessels (Ali et al, ; Baron et al, ; Harrington et al, ; Li et al, ; Kirkby et al, ). Initially, this was a surprising discovery as PPARβ was thought to be a pathway that regulates gene induction rather than acute signalling events; however, now we know that PPARβ activation leads to the engagement of both genomic and non‐genomic pathways (Mitchell et al, ).…”

Section: Role Of Cox‐2 In Cardiovascular Protection and The Cardiovasmentioning

confidence: 87%

Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system

Mitchell¹,

Kirkby²

2018

British J Pharmacology

178

123

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Eicosanoids represent a diverse family of lipid mediators with fundamental roles in physiology and disease. Within the eicosanoid superfamily are prostanoids, which are specifically derived from arachidonic acid by the enzyme cyclooxygenase (COX). COX has two isoforms; COX-1 and COX-2. COX-2 is the therapeutic target for the nonsteroidal anti-inflammatory drug (NSAID) class of pain medications. Of the prostanoids, prostacyclin, first discovered by Sir John Vane in 1976, remains amongst the best studied and retains an impressive pedigree as one of the fundamental cardiovascular protective pathways. Since this time, we have learnt much about how eicosanoids, COX enzymes and prostacyclin function in the cardiovascular system, knowledge that has allowed us, for example, to harness the power of prostacyclin as therapy to treat pulmonary arterial hypertension and peripheral vascular disease. However, there remain many unanswered questions in our basic understanding of the pathways, and how they can be used to improve human health. Perhaps, the most important and controversial outstanding question in the field remains; 'how do NSAIDs produce their much publicized cardiovascular side-effects?' This review summarizes the history, biology and cardiovascular function of key eicosanoids with particular focus on prostacyclin and other COX products and discusses how our knowledge of these pathways can applied in future drug discovery and be used to explain the cardiovascular side-effects of NSAIDs.

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“…Inhibition of intracellular calcium mobilization in platelets and vascular smooth muscle cells leads to attenuated aggregation response [ 60 ] and vessel dilation, respectively, both of which contribute to the anti-thrombotic effects of PGI 2 . Like the surface IP receptor, the intracellular receptor PPARβ/ δ has also been reported to regulate signaling events during platelet activation and vessel dilation [ [61] , [62] , [63] ].…”

Section: Roles Of Mas Receptor Pgi 2 and Sirt1 mentioning

confidence: 99%

Novel anti-thrombotic mechanisms mediated by Mas receptor as result of balanced activities between the kallikrein/kinin and the renin-angiotensin systems

Fang

2020

Pharmacological Research

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Cyclooxygenase-2 Selectively Controls Renal Blood Flow Through a Novel PPARβ/δ-Dependent Vasodilator Pathway

Abstract: Supplemental Digital Content is available in the text.

Cited by 34 publications

References 41 publications

Differential properties of E prostanoid receptor‐3 and thromboxane prostanoid receptor in activation by prostacyclin to evoke vasoconstrictor response in the mouse renal vasculature

Differential properties of E prostanoid receptor‐3 and thromboxane prostanoid receptor in activation by prostacyclin to evoke vasoconstrictor response in the mouse renal vasculature

Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system

Novel anti-thrombotic mechanisms mediated by Mas receptor as result of balanced activities between the kallikrein/kinin and the renin-angiotensin systems

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