20-HETE (20-Hydroxyeicosatetraenoic acid) is a major metabolite of arachidonic acid produced by CYP4A and CYP4F that acts as a potent vasoconstrictor. It also plays roles in sodium transport, endothelial dysfunction, oxidative stress, cell proliferation, vascular hypertrophy, inflammation, and angiogenesis. Increased levels of 20-HETE are associated with cerebral, renal, and cardiovascular diseases, including hypertension, stroke, coronary artery disease, myocardial infarction, acute kidney failure, chronic kidney disease, polycystic kidney disease, as well as conditions that are associated with hypertrophy and hyperplasia such as tumor growth and metastasis, end-organ damage, and fibrosis.
Because 20-HETE (20-Hydroxyeicosatetraenoic acid) is rapidly esterified into membrane phospholipids, identifying the receptor it activated remained elusive until Garcia et al. designed a shrewd, multi-step strategy to cross-link a fluorescently tagged, photoactive 20-HETE antagonist to the cell surface, isolate the labeled proteins, and use proteomics as well as bioinformatics to identify its binding partners.4 The Schwartzman lab at New York Medical College has demonstrated that 20-HETE binding to GPR75 promotes dissociation of the Gq subunit and the association of GPCR-kinase interacting protein-1 (GIT1) to GPR75, which facilitates the release of c-Src from the GPR75 receptor freeing it to phosphorylate EGFR, activating the MAPK/IKKβ/NF-κB pathway (Figure 1). This signaling pathway is related to uncoupling of eNOS, endothelial dysfunction, and increased expression of angiotensin-converting enzyme (ACE). 20-HETE activation of NF-κB signaling also induces the expression of cellular adhesion molecules and cytokines, thereby promoting inflammation. They have also shown in endothelial and smooth muscle cells that 20-HETE activates the classical Gq-coupled PLC/IP3 signaling pathway that results in release of calcium from intracellular stores, which leads to a vasoconstrictor response (Figure 1).
