Control of coronary vascular resistance by eicosanoids via a novel GPCR

Abstract

Arachidonic acid metabolites epoxyeicosatrienoates (EETs) and hydroxyeicosatetraenoates (HETEs) are important regulators of myocardial blood flow and coronary vascular resistance (CVR), but their mechanisms of action are not fully understood. We applied a chemoproteomics strategy using a clickable photoaffinity probe to identify G protein coupled receptor 39 (GPR39) as a microvascular smooth muscle cell (mVSMC) receptor selective for two endogenous eicosanoids, 15-HETE and 14,15-EET, which act on the receptor to oppose each other's activity. The former increases mVSMC intracellular calcium via GPR39 and augments coronary microvascular resistance, and the latter inhibits these actions. Furthermore, we find that the efficacy of both ligands is potentiated by zinc acting as an allosteric modulator. Measurements of coronary perfusion pressure (CPP) in GPR39-null hearts using the Langendorff preparation indicate the receptor senses these eicosanoids to regulate microvascular tone. These results implicate GPR39 as an eicosanoid receptor and key regulator of myocardial tissue perfusion. Our findings will have a major impact on understanding the roles of eicosanoids in cardiovascular physiology and disease and provide an opportunity for the development of novel GPR39-targeting therapies for cardiovascular disease.

GPR39 Deficiency Impairs Memory and Alters Oxylipins and Inflammatory Cytokines Without Affecting Cerebral Blood Flow in a High-Fat Diet Mouse Model of Cognitive Impairment

“…However, the profile of oxylipins increased by HFD and GPR39 deletion is suggestive of increased neuroinflammation. We recently reported that GPR39 is an oxylipins receptor ( Alkayed et al, 2022 ); therefore, we report here valuable and unique oxylipins data that point to specific pathways altered in brain and plasma by HFD and GPR39 deletion, as potential mediators of cognitive impairment in these models. Another limitation is that we used a global GPR39 KO mouse model.…”

“…These diverse roles are believed to be related to the function of GPR39 as a receptor for zinc. More recently, we found that GPR39 also serves as a dual sensor for two eicosanoids with opposing actions on microvascular tone: the vasodilator 14,15-epoxyeicosatrienoate (14,15-EET) and vasoconstrictor 15-hydroxyeicosatetraenoate (15-HETE) ( Alkayed et al, 2022 ).…”

“…Thirty-six 4-month-old male mice of one of three genotypes: homozygous GPR39 KO, heterozygous (Het), or WT littermates were used in this study. The GPR39 mutant mice were generated by Cyagen Biosciences (Santa Clara, CA, United States) using a CRISPR/Cas9 deletion strategy and zygotic injections, which have previously been reported ( Alkayed et al, 2022 ).…”

“…We recently reported that the G protein-coupled receptor 39 (GPR39) is a dual-ligand receptor regulated by AA-derived oxylipins with opposing actions on inflammation and microvascular tone ( Xu et al, 2021 ; Alkayed et al, 2022 ). GPR39 is a member of the ghrelin family of G protein-coupled receptors (GPCRs) that has recently been implicated in VCI ( Davis et al, 2021a ).…”

Data_Sheet_1.pdf

“…We recently reported that the G protein-coupled receptor 39 (GPR39) is a dual-ligand receptor regulated by AAderived oxylipins with opposing actions on inflammation and microvascular tone (Xu et al, 2021;Alkayed et al, 2022). GPR39 is a member of the ghrelin family of G proteincoupled receptors (GPCRs) that has recently been implicated in VCI (Davis et al, 2021a).…”