Vascular actions of 20-HETE

Abstract

20-hydroxyeicosatetraenoic acid (20-HETE) is a metabolite of arachidonic acid that exhibits a myriad of biological effects in the vascular system. This review discusses the current knowledge related to the effects of 20-HETE on vascular reactivity, activation, and remodeling, as well as its role in vascular inflammation and angiogenesis. The information explaining how 20-HETE and the renin-angiotensin system interact to promote hypertension, vasoconstriction, and vascular dysfunction is summarized in this article. 20-HETE enhances vascular inflammation and injury in models of diabetes, ischemia/reperfusion, and cerebrovascular oxidative stress. Recent studies also established a role for 20-HETE in normal and pathological angiogenesis conditions. This review will also discuss the molecular mechanisms through which 20-HETE induces these vascular actions. Potential additional studies are suggested to address shortcomings in the current knowledge of 20-HETE in the vascular system.

20-HETE in the regulation of vascular and cardiac function

“…They showed that 20-HETE was more efficacious than dietary free fatty acids in activating FFAR1 when tested for induction of Ca 2+ transients and in promoting glucose-stimulated insulin secretion in pancreatic β-cells. However, 20-HETE activated this receptor at micromolar to millimolar concentrations; much higher than the reported concentrations of 20-HETE that activate GPR75 (Garcia et al, 2017) and exert biological activities such as vasoconstriction and endothelial dysfunction (Garcia & Schwartzman, 2017; Hoopes et al, 2015). It is possible that the binding of 20-HETE to FFAR1, the expression of which is limited to the pancreatic α and β cells and to the enteroendocrine cells within the intestine, becomes functionally relevant under conditions of high levels of 20-HETE.…”

“…20-HETE is a vasoactive lipid molecule and a prominent constrictor of microcirculatory districts where its production is prominent. Its effects on vascular function are multifaceted and include stimulation of smooth muscle contractility, migration and proliferation, as well as modulation of endothelial cell dysfunction and inflammation (Fan et al, 2016; Hoopes, Garcia, Edin, Schwartzman, & Zeldin, 2015; Miyata & Roman, 2005). Such effects may have significant implications with regard to the regulation of the cardiovascular system and the development of CVDs.…”

GPR75 Identified as the First 20-HETE Receptor

“…This leads to uncoupling of eNOS, endothelial dysfunction, and increased expression of ACE. 8 Similarly, the authors found that 20-HETE activation of GPR75 in rat aortic VSMCs promoted disassociation of Gα q/11 which is known to activate the PLC/DAG/IP3/PKC pathway to increase intracellular calcium and the vasoconstrictor response to Gq receptor agonists. They also demonstrated increased association of PKCα and c-Src and enhanced tyrosine phosphorylation of the BK β channel subunit in VSMCs.…”

“…6 Subsequent studies indicating that the vasoconstrictor, and natriuretic actions of 20-HETE are PLC/PKC-dependent, while its effects on cell migration and proliferation, endothelial dysfunction, inflammation are associated with activation of the c-Src and MAPK pathways, futher suggest that 20-HETE act via GPRs. 4,5,7,8 However, the identification of this elusive receptor using binding studies has been fraught with difficulties because 20-HETE is rapidly esterified into membrane phospholipids, avidly binds to proteins, and distributes intracellularly. 4 Garcia et al .…”

20-HETE-induced mitochondrial superoxide production and inflammatory phenotype in vascular smooth muscle is prevented by glucose-6-phosphate dehydrogenase inhibition

“…20-HETE is proinflammatory and it regulates vascular and renal function (49). It also plays a critical role in the pathogenesis of systemic hypertension, renal stenosis, and atherosclerosis (27,63,65). 20-HETE increased by hypoxia inhibits hypoxia-induced pulmonary artery constriction (69).…”