Lipoxin and Resolvin Receptors Transducing the Resolution of Inflammation in Cardiovascular Disease

Abstract

A non-resolving inflammation results in a chronic inflammatory response, characteristic of atherosclerosis, abdominal aortic aneurysms and several other cardiovascular diseases. Restoring the levels of specialized proresolving mediators to drive the chronic cardiovascular inflammation toward resolution is emerging as a novel therapeutic principle. The lipid mediators lipoxins and resolvins exert their proresolving actions through specific G-protein coupled receptors (GPCR). So far, four GPCR have been identified as the receptors for lipoxin A4 and the D- and E-series of resolvins, namely ALX/FPR2, DRV1/GPR32, DRV2/GPR18, and ERV1/ChemR23. At the same time, other pro-inflammatory ligands also activate some of these receptors. Recent studies of genetic targeting of these receptors in atherosclerotic mouse strains have revealed a major role for proresolving receptors in atherosclerosis. The present review addresses the complex pharmacology of these four proresolving GPCRs with focus on their therapeutic implications and opportunities for inducing the resolution of inflammation in cardiovascular disease.

Resolution of Inflammation in Neurodegenerative Diseases: The Role of Resolvins

“…Noteworthy, both E-series resolvins (e.g., RvE1 and RvE2), which are bioactive oxygenated lipid products of EPA, and D-series resolvins (e.g., RvD1, RvD2, RvD3, and RvD5), which are DHA derivatives, exert their proresolving action through transmembrane G-protein-coupled receptors (GPCRs). Currently, four receptors for resolvins are known, that is, A lipoxin and formyl peptide receptor 2 (ALX/FPR2), D resolvin receptor 1(DRV1)/GPR32, D-resolvin receptor 2 (DRV2)/GPR18, and chemokine-like receptor 1 (CMKLR1), which is also referred to as ChemR23 or ERV1 [16].…”

“…Available evidence suggests that the proresolving action mediated by RvE2 is more selectively directed towards neutrophils, as compared to that mediated by RvE1. However, whether RvE1 and RvE2 may share the same receptor and signaling cascade remains unclear [16,19].…”

“…D-series resolvins display a variable affinity for three different GPCRs (i.e., ALX/FPR2, DRV1/GPR32, and DRV2/GPR18). RvD1 and RvD3 transduce their signal through both ALX/FPR2 and DRV1/GPR32, whereas RvD2 and RvD5 signal through DRV2/GPR18 and DRV1/GPR32, respectively [16]. The activation of the ALX/FPR2 pathway inhibits the p38 mitogen-activated protein kinase (MAPK) phosphorylation, counteracting the ability of neutrophils and macrophages to migrate and produce proinflammatory mediators [4,6,20,21].…”

Reversal of Epithelial–Mesenchymal Transition by Natural Anti-Inflammatory and Pro-Resolving Lipids

“…Pro-resolving lipids can be useful agent against cancer and EMT of cancer has been studied since cancer is understood as a non-resolving disease [6,280] Here, we briefly introduced the effect of pro-resolving lipids on EMT of cancer cells and emphasized natural sources of pro-resolving lipids ( Table 2). Pro-resolving lipids are generally known to act via GPCR receptors such as BLT1, CMKLR1, FPRL1 (ALX/FPR2), GPR18, and GPR3 [41,281]. CMKLR1 is a receptor with high affinity for RvE1, as measured via radioligand-binding assay (Kd = 11.3-5.4 nM) [282,283].…”

Omega‐3 fatty acids, cardiovascular risk, and the resolution of inflammation

“…SPMs include, for example, the D-series resolvins (Rvs), derived from the v-3 fatty acid docosahexaenoic acid (DHA), and the E-series Rvs from EPA, as first described by Serhan et al (12). With the activation of specific receptors (13), SPMs actively terminate the inflammatory reactions by means of, for example, removal of dead cells (efferocytosis), increased phagocytosis, and leukocyte egress from the site of inflammation (11,14). The benefits of SPM-stimulated macrophage phagocytosis may extend beyond cardiovascular disease, as demonstrated by an enhanced endogenous clearance of tumor cell debris by SPMs (15).…”