20-HETE Signals Through G-Protein–Coupled Receptor GPR75 (G q ) to Affect Vascular Function and Trigger Hypertension
Authors: Jorge H Capdevila
Brian Shkolnik
Victor Garcia
Shyam K Gandham
Artiom Gruzdev
Michal Laniado Schwartzman
John R Falck
Frank Fan Zhang
N Rami Reddy
Rambabu Dakarapu
Varunkumar Pandey
Ankit Gilani
Joan P Graves
Darryl C Zeldin
Journal: Circulation Research (2017)
Discipline: CLINICAL MEDICINE
Keywords: cardiovascular diseases; cytochrome P-450 enzyme system; hypertension; receptor, epidermal growth factor; vascular remodeling.
Affiliations: From the Department of Pharmacology, New York Medical College School of Medicine, Valhalla (V.G., A.G., B.S., V.P., F.F.Z., M.L.S.); Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas (R.D., S.K.G., N.R.R., J.R.F.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (J.P.G., A.G., D.C.Z.); and Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (J.H.C.)., From the Department of Pharmacology, New York Medical College School of Medicine, Valhalla (V.G., A.G., B.S., V.P., F.F.Z., M.L.S.); Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas (R.D., S.K.G., N.R.R., J.R.F.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (J.P.G., A.G., D.C.Z.); and Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (J.H.C.). .

Abstract:  Rationale: 20-Hydroxyeicosatetraenoic acid (20-HETE), one of the principle cytochrome P450 eicosanoids, is a potent vasoactive lipid whose vascular effects include stimulation of smooth muscle contractility, migration, and proliferation, as well as endothelial cell dysfunction and inflammation. Increased levels of 20-HETE in experimental animals and in humans are associated with hypertension, stroke, myocardial infarction, and vascular diseases. Objective: To date, a receptor/binding site for 20-HETE has been implicated based on the use of specific agonists and antagonists. The present study was undertaken to identify a receptor to which 20-HETE binds and through which it activates a signaling cascade that culminates in many of the functional outcomes attributed to 20-HETE in vitro and in vivo. Methods and results: Using crosslinking analogs, click chemistry, binding assays, and functional assays, we identified G-protein receptor 75 (GPR75), currently an orphan G-protein-coupled receptor (GPCR), as a specific target of 20-HETE. In cultured human endothelial cells, 20-HETE binding to GPR75 stimulated Gαq/11 protein dissociation and increased inositol phosphate accumulation and GPCR-kinase interacting protein-1-GPR75 binding, which further facilitated the c-Src-mediated transactivation of epidermal growth factor receptor. This results in downstream signaling pathways that induce angiotensin-converting enzyme expression and endothelial dysfunction. Knockdown of GPR75 or GPCR-kinase interacting protein-1 prevented 20-HETE-mediated endothelial growth factor receptor phosphorylation and angiotensin-converting enzyme induction. In vascular smooth muscle cells, GPR75-20-HETE pairing is associated with Gαq/11- and GPCR-kinase interacting protein-1-mediated protein kinase C-stimulated phosphorylation of MaxiKβ, linking GPR75 activation to 20-HETE-mediated vasoconstriction. GPR75 knockdown in a mouse model of 20-HETE-dependent hypertension prevented blood pressure elevation and 20-HETE-mediated increases in angiotensin-converting enzyme expression, endothelial dysfunction, smooth muscle contractility, and vascular remodeling. Conclusions: This is the first report to identify a GPCR target for an eicosanoid of this class. The discovery of 20-HETE-GPR75 pairing presented here provides the molecular basis for the signaling and pathophysiological functions mediated by 20-HETE in hypertension and cardiovascular diseases. 

Retracted: No

PubPeer comments:
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