G-Protein Coupled Receptor Targeting on Myeloid Cells in Atherosclerosis

Abstract

Atherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVDs), is a lipid-driven, inflammatory disease of the large arteries. Gold standard therapy with statins and the more recently developed proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have improved health conditions among CVD patients by lowering low density lipoprotein (LDL) cholesterol. Nevertheless, a substantial part of these patients is still suffering and it seems that ‘just’ lipid lowering is insufficient. The results of the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) have now proven that inflammation is a key driver of atherosclerosis and that targeting inflammation improves CVD outcomes. Therefore, the identification of novel drug targets and development of novel therapeutics that block atherosclerosis-specific inflammatory pathways have to be promoted. The inflammatory processes in atherosclerosis are facilitated by a network of immune cells and their subsequent responses. Cell networking is orchestrated by various (inflammatory) mediators which interact, bind and induce signaling. Over the last years, G-protein coupled receptors (GPCRs) emerged as important players in recognizing these mediators, because of their diverse functions in steady state but also and specifically during chronic inflammatory processes – such as atherosclerosis. In this review, we will therefore highlight a selection of these receptors or receptor sub-families mainly expressed on myeloid cells and their role in atherosclerosis. More specifically, we will focus on chemokine receptors, both classical and atypical, formyl-peptide receptors, the chemerin receptor 23 and the calcium-sensing receptor. When information is available, we will also describe the consequences of their targeting which may hold promising options for future treatment of CVD.

Decoding the transcriptome of atherosclerotic plaque at single-cell resolution

“…IL6 , a key inflammatory cytokine associated with plaque 41 , is the most upregulated gene. Furthermore, ACKR1, highly upregulated in many PA ECs, binds and internalizes numerous chemokines and facilitates their presentation on the cell surface in order to boost leukocyte recruitment and augment inflammation 42 . Antigen presentation on ECs via HLA-DQA1 (MHC class II molecule) supports activation and exhaustion of CD4+ T-cells 43,44 as previously described.…”

Periodontitis related to cardiovascular events and mortality: a long-time longitudinal study

“…Deaths by CVDs have decreased during the latest 60 years, as a result of preventive care and advances in medicine [29]. Many older individuals are using preventive medications that may delay or even prevent a CVD event from occurring [30].…”

The resolution of inflammation through omega-3 fatty acids in atherosclerosis, intimal hyperplasia, and vascular calcification

“…Nevertheless, these findings illustrate the complexity of proresolving signalling in atherosclerosis, which is regulated by means of both ligand availability, receptor expression, and compensatory mechanisms. In addition to RvE1, ChemR23 is also activated by the adipokine chemerin [47] as well as chemerin-derived peptides [48], which induce differential responses depending on peptide length. Notably, the ChemR23 receptor agonist chemerin-p decreases atherosclerosis after 4 weeks treatment in apoE knock-out mice [49].…”