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Review
. 2022:94:1-25.
doi: 10.1016/bs.apha.2022.02.003. Epub 2022 Mar 30.

The CYP/20-HETE/GPR75 axis in hypertension

Ghezal Froogh  1 , Victor Garcia  1 , Michal Laniado Schwartzman  2
Affiliations
Review

The CYP/20-HETE/GPR75 axis in hypertension

Ghezal Froogh et al. Adv Pharmacol. 2022.

Abstract

20-Hydroxyeicosatetraenoic acid (20-HETE) is a bioactive lipid generated from the ω-hydroxylation of arachidonic acid (AA) by enzymes of the cytochrome P450 (CYP) family, primarily the CYP4A and CYP4F subfamilies. 20-HETE is most notably identified as a modulator of vascular tone, regulator of renal function, and a contributor to the onset and development of hypertension and cardiovascular disease. 20-HETE-mediated signaling promotes hypertension by sensitizing the vasculature to constrictor stimuli, inducing endothelial dysfunction, and potentiating vascular inflammation. These bioactions are driven by the activation of the G-protein coupled receptor 75 (GPR75), a 20-HETE receptor (20HR). Given the capacity of 20-HETE signaling to drive pro-hypertensive mechanisms, the CYP/20-HETE/GPR75 axis has the potential to be a significant therapeutic target for the treatment of hypertension and cardiovascular diseases associated with increases in blood pressure. In this chapter, we review 20-HETE-mediated cellular mechanisms that promote hypertension, highlight important data in humans such as genetic variants in the CYP genes that potentiate 20-HETE production and describe recent findings in humans with 20HR/GPR75 mutations. Special emphasis is given to the 20HR and respective receptor blockers that have the potential to pave a path to translational and clinical studies for the treatment of 20-HETE-driven hypertension, and obesity/metabolic syndrome.

Keywords: 20-HETE; Cardiovascular disease; Cytochrome P450; GPR75; Hypertension.

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Conflict of interest statement

Conflict of interest statement The authors have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
20-HETE Synthesis and Target Organs. 20-HETE producing CYP isoforms CYP4A and CYP4F reside across the vasculature in vascular smooth muscle cells (VSMCs). 20-HETE elicits its bioactions across various target organs/tissues including the kidney, heart, brain and adipose. Elevation in 20-HETE is associated with the onset and development of hypertension, obesity, stroke and myocardial infarction.
Fig. 2
Fig. 2
20-HETE Receptor (GPR75) Signaling in Endothelial Cells. The binding to and activation of the 20-HETE receptor (GPR75) via 20-HETE leads to Gαq/11 driven signaling and the transactivation of the epidermal growth factor receptor (EGFR) via a GIT1 –/c-SRC-dependent pathway that stimulates the activation of MAPK and the IKK complex. Activated IKK initiates two events; firstly, IKK triggers the translocation of NF-KB to the nucleus where it binds the promotor region of the angiotensin converting enzyme (ACE) gene leading to the increased transcription of ACE. Secondly, IKK activation promotes the endothelial nitric oxide synthase (eNOS) uncoupling through recruitment of the chaperone protein HSP90 away from eNOS resulting in decreased nitric oxide (NO) bioavailability. Moreover, 20-HETE receptor signaling promotes the activation protein kinase C (PKC) driven mechanisms including increases in NADPH oxidase-derived ROS generation. Taken together, these signaling events promote endothelial dysfunction and initiate pro-inflammatory signaling pathways that promote the development of hypertension and inflammation.
Fig. 3
Fig. 3
The postulated outcomes of 20-HETE-GPR75 pairing in the vasculature and its contribution to hypertension and related cardiovascular diseases.
See this image and copyright information in PMC

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