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. 2022 Aug 1;80(2):276-293.
doi: 10.1097/FJC.0000000000001265.

Activation of GPR75 Signaling Pathway Contributes to the Effect of a 20-HETE Mimetic, 5,14-HEDGE, to Prevent Hypotensive and Tachycardic Responses to Lipopolysaccharide in a Rat Model of Septic Shock

Bahar Tunctan  1 , Sefika Pinar Senol  1 , Meryem Temiz-Resitoglu  1 , Dilsah Ezgi Yilmaz  1 , Demet Sinem Guden  1 , Omer Bahceli  1 , Mehmet Furkan Horat  1 , Seyhan Sahan-Firat  1 , Ayse Nihal Sari  1 , John R Falck  2 , Raghunath Reddy Anugu  2 , Kafait U Malik  3
Affiliations

Activation of GPR75 Signaling Pathway Contributes to the Effect of a 20-HETE Mimetic, 5,14-HEDGE, to Prevent Hypotensive and Tachycardic Responses to Lipopolysaccharide in a Rat Model of Septic Shock

Bahar Tunctan et al. J Cardiovasc Pharmacol. .

Abstract

The orphan receptor, G protein-coupled receptor (GPR) 75, which has been shown to mediate various effects of 20-hydroxyeicosatetraenoic acid (20-HETE), is considered as a therapeutic target in the treatment of cardiovascular diseases in which changes in the production of 20-HETE play a key role in their pathogenesis. Our previous studies showed that 20-HETE mimetic, N -(20-hydroxyeicosa-5[Z],14[Z]-dienoyl)glycine (5,14-HEDGE), protects against vascular hyporeactivity, hypotension, tachycardia, and arterial inflammation induced by lipopolysaccharide (LPS) in rats. This study tested the hypothesis that the GPR75 signaling pathway mediates these effects of 5,14-HEDGE in response to systemic exposure to LPS. Mean arterial pressure reduced by 33 mm Hg, and heart rate increased by 102 beats/min at 4 hours following LPS injection. Coimmunoprecipitation studies demonstrated that (1) the dissociation of GPR75/Gα q/11 and GPR kinase interactor 1 (GIT1)/protein kinase C (PKC) α, the association of GPR75/GIT1, large conductance voltage and calcium-activated potassium subunit β (MaxiKβ)/PKCα, MaxiKβ/proto-oncogene tyrosine-protein kinase (c-Src), and epidermal growth factor receptor (EGFR)/c-Src, MaxiKβ, and EGFR tyrosine phosphorylation were decreased, and (2) the association of GIT1/c-Src was increased in the arterial tissues of rats treated with LPS. The LPS-induced changes were prevented by 5,14-HEDGE. N -[20-Hydroxyeicosa-6( Z ),15( Z )-dienoyl]glycine, a 20-HETE antagonist, reversed the effects of 5,14-HEDGE in the arterial tissues of LPS-treated rats. Thus, similar to 20-HETE, by binding to GPR75 and activating the Gα q/11 /PKCα/MaxiKβ, GIT1/PKCα/MaxiKβ, GIT1/c-Src/MaxiKβ, and GIT1/c-Src/EGFR signaling pathways, 5,14-HEDGE may exert its protective effects against LPS-induced hypotension and tachycardia associated with vascular hyporeactivity and arterial inflammation.

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Conflict of interest statement

The authors report no conflicts of interest.

Comment in

  • Turn Up the HETE on Septic Shock.
    Thomas K, Strong L, Fan F, Roman RJ. Thomas K, et al. J Cardiovasc Pharmacol. 2022 Aug 1;80(2):206-209. doi: 10.1097/FJC.0000000000001300. J Cardiovasc Pharmacol. 2022. PMID: 35575984 Free PMC article.

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